Combination treatments

ABSTRACT

A method of treating a subject in need thereof, is carried out by (a) administering said subject a therapeutic intervention (e.g., an active agent) in a treatment effective amount; and concurrently (b) administering said subject caloric vestibular stimulation in a treatment effective amount, said caloric vestibular stimulation administered so as to enhance the efficacy of said active agent. In some embodiments, the caloric vestibular stimulation is administered as an actively controlled time varying waveform.

RELATED APPLICATIONS

This application is a continuation of and claims priority to U.S. patentapplication Ser. No. 14/847,580, now issued as U.S. Pat. No. 9,744,074,filed on Sep. 8, 2015, which in turn claims priority to U.S. Pat. No.9,168,171, filed on Jul. 24, 2013, which is a 35 U.S.C. § 371 nationalphase entry of PCT Application PCT/US2011/065338, filed Dec. 16, 2011,and published in English on Jun. 21, 2012, as International PublicationNo. WO 2012/083106, and which claims priority to U.S. Provisional PatentApplication No. 61/424,474, filed Dec. 17, 2010; 61/498,131, filed Jun.17, 2011; 61/497,761, filed Jun. 16, 2011; 61/424,132, filed Dec. 17,2010; 61/498,096, filed Jun. 17, 2011; 61/424,326, filed Dec. 17, 2010;61/498,080, filed Jun. 17, 2011; 61/498,911, filed Jun. 20, 2011 and61/498,943, filed Jun. 20, 2011; U.S. patent application Ser. No.12/970,312, filed Dec. 16, 2010 and Ser. No. 12/970,347, filed Dec. 16,2010 and PCT Application No. PCT/US2010/060764, filed Dec. 16, 2010; thedisclosure of each of which is incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The present invention concerns methods and apparatus for carrying outcombination treatments with caloric vestibular stimulation and a drug,particularly an oral drug.

BACKGROUND OF THE INVENTION

Caloric vestibular stimulation (CVS) has been widely and safely utilizedfor more than a century for diagnostic purposes, particularly in theemergency room to detect brain function after trauma. CVS activates thesensory organs of the vestibular system (VS) located within the innerear. The core elements consist of the semi-circular canals, which senserotational motion, and the otoliths, which sense linear acceleration.Motion within the semi-circular canals is detected through motion ofinternal fluid (endolymph), which in turn activates hair cells thatgenerate electrical signals, which are then transmitted via the 8thcranial nerve to the brainstem and widely throughout the cerebellum andcortical regions. In CVS, irrigation of the outer ear canal with warm orcold water changes the density of the endolymph in the semi-circularcanal of the inner ear, which in turn activates the pathways notedabove. Nystagmus, or the vestibulo-ocular reflex, is an easily observedresult of CVS where the eyes move spontaneously, even if the patient isunconscious. See generally L. Patten, Vestibulo-ocular reflex paths, Br.J. Ophthalmol. 16, 257 (1932).

There have been intriguing (but largely anecdotal) reports of using CVSas a therapeutic measure. See generally L. Rogers and L. Smith, PCTAppl. Pub. No. WO 2009/020862. Survey articles document a variety ofoutcomes and discuss some of the mechanisms involved (Miller et al.,Acta Neuropsychiatria 19:183-203 (2007); Been et al., Brain ResearchReviews 56 346-36 (2007)). Squirting or blowing warm/cold water/air intoa patient's ear, however, is crude, does not provide closely controlledthermal activity, and is not consistent with medical dosing.

CVS is known to activate specific brainstem, cerebellar and corticalsites, which have therapeutic potential, as demonstrated throughfunctional imaging (Bottini et al., Exp Brain Res 99: 164-169 (1994);Bense et al., Ann NY Acad Science 1004: 440-445 (2003); Dieterich etal., Brain, 131, 2538-2552 (2008); Hum Brain Mapp (September 2009);Naito, Cortical correlates of vestibulo-ocular reflex modulation: A PETstudy. Brain 126 (2003)).

In addition, vestibular stimulation is also known to release importantneurotransmitters (e.g., serotonin, acetylcholine, histamine,endorphins, vasopressin and dopamine) (MA Fu-rong et al., Chin Med J120(2):120-124 (2007); Horii et al., J. Neurophysiol. 72, 605-611(1994); Tabet, Age and Aging, 35: 336-338 (2006); Horii et al., JNeurophysiol 70 1822-1826 (1993); Horii et al., Brain Research 914:179-184 (2001)).

In contrast to both pharmaceutical treatment and neurostimulationdevices which employ electrical signals, CVS appears to have anadvantage: although nystagmus habituates with repetition of CVS (Naitoet al., supra (2003)), the vestibular neurological response appears notto be subject to such habituation or accommodation. (Emani-Nouri, ActaOtolaryngologica 76, 183-189 (1973)). In addition, CVS does not have thepotential for side effects in the same manner that a pharmaceuticaldoes. Yet, CVS has not attained wide-spread use for therapeuticpurposes. Hence, there remains a need for methods to utilize caloricvestibular stimulation for therapeutic purposes.

SUMMARY OF THE INVENTION

The present invention provides a method of treating a subject in needthereof, comprising: (a) administering said subject an active agent (orother therapeutic intervention) in a treatment effective amount; andconcurrently (b) administering said subject caloric vestibularstimulation in a treatment effective amount. In the present invention,the caloric vestibular stimulation is administered as an “adjuvant,”preferably to enhance the efficacy of the active agent (or othertherapeutic intervention).

A further aspect of the invention that can be carried out in combinationwith the above is a method comprising: (a) selecting a first thermalstimulus for the caloric vestibular stimulator; (b) assessing orobserving efficacy of the selected thermal stimulus pattern; and then(c) selecting a subsequent thermal stimulus for the caloric vestibularstimulator different from the previously selected thermal stimuluspattern. Stated otherwise, an aspect of the invention is a method oftreating a subject in need thereof (e.g., a subject afflicted with adisorder or condition as described herein), comprising: (a)administering said subject a first thermal stimulus with a caloricvestibular stimulator; (b) assessing or observing efficacy of theselected stimulus pattern; and then (c) administering said subject asubsequent thermal stimulus with the caloric vestibular stimulator(preferably a thermal stimulus effective to treat the condition ordisorder), said subsequent thermal stimulus optionally, but in someembodiments preferably, different from the previously selected thermalstimulus pattern.

In some embodiments, the step of assessing or observing efficacycomprises detecting at least physiological parameter, examples of whichinclude but are not limited to subjective pain score, nystagmographydata, blood A1c data, EEG data, MRI data, pulse oximetry data, bloodpressure data, heart rate data, heart rate variability data, cerebralblood flow data, galvanic skin response (GSR) data, blood chemistry data(such as blood or serum glucose concentration data), saliva chemistrydata, urine chemistry data, etc.

In some embodiments, the step of selecting a subsequent thermal stimuluspattern is carried out from a predetermined set of thermal stimuluspatterns.

Some embodiments further comprise the step of modifying a selectedmember of the predetermined set based on observed efficacy of the priorselected stimulus pattern.

Some embodiments further comprise (d) iteratively repeating steps (b) to(c) based on assessed or observed efficacy.

Some embodiments further comprise: (e) terminating the iterativerepetition when one or more termination criteria are met.

In some embodiments, the iterative repetition is carried out in thecourse of a chronic program of treating a subject with the caloricvestibular stimulator.

In some embodiments, each thermal stimulus is an independently selectedwaveform stimulus (e.g., a square waveform or time-varying waveformstimulus).

In some embodiments, the first thermal stimulus is a square waveformstimulus.

In some embodiments, at least one (or a plurality, or all) of thesubsequent thermal stimulus or stimuli is a time-varying waveformstimulus (e.g., has a ramped leading edge). In some embodiments, atleast one, or a plurality, of the waveform stimulus or stimuli comprisesa first time-varying waveform followed by at least a second time-varyingwaveform.

In some embodiments, the waveform stimulus (e.g., each of the first andsecond time varying waveforms, which may be the same or different), hasa duration of from 1 or 2 minutes to 10 or 20 minutes, or more, and anamplitude of from 5 to 17, 22 or 24 degrees Centigrade.

In some embodiments the first thermal stimulus comprises a coolingstimulus (e.g., a cooling time varying or waveform stimulus; acombination cooling and warming time varying or waveform stimulus), andsaid subsequent thermal stimulus comprises a warming stimulus (e.g., awarming time varying or waveform stimulus; a combination warming andcooling time varying waveform stimulus).

In some embodiments the first thermal stimulus comprises a warmingstimulus (e.g., a warming time varying or waveform stimulus; acombination warming and cooling time varying or waveform stimulus), andsaid subsequent thermal stimulus comprises a cooling stimulus (e.g., acooling time varying or waveform stimulus; a combination cooling andwarming time varying or waveform stimulus).

In some embodiments, the first and/or subsequent thermal stimulus areconfigured to maintain a vestibular stimulation of the subject for atleast four or five minutes.

In some embodiments, the vestibular stimulation for at least four orfive minutes is sufficient to alter a vestibular phasic firing rate toinduce nystagmus over a period of at least four or five minutes.

In some embodiments, the nystagmus is sufficient to be detected, and/oris detected, using videonystagmography and/or electronystagmography.

A further aspect of the invention is a computer-readable mediumcomprising instructions to cause a processor to carry out a methodaccording to any preceding claim.

A further aspect of the invention is a device comprising a processorprogrammed to carry out a method according to any preceding claim.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects and aspects of the present invention areexplained in greater detail in the drawings herein and the specificationset forth below. All patent references cited herein are specificallyintended to be incorporated herein by reference in their entirety.

FIG. 1 is a block diagram of a vestibular stimulation device accordingto some embodiments of the present invention.

FIGS. 2-12 are screenshots illustrating various functionalities of acontroller according to some embodiments of the present invention,wherein the controller comprises an interactive touchscreen.

FIG. 2 depicts a startup screen wherein the current time is shown in theupper right-hand corner of the screen.

FIG. 3 depicts a waveform module screen wherein the user has generated athermal waveform by drawing the desired waveform on the interactivetouch screen and wherein the waveform module has identified fourteenwaveform modulation points (gray diamonds).

FIG. 4 depicts a waveform module screen wherein the thermal waveformdepicted in FIG. 3 has been modified by selecting the third waveformmodulation point of the thermal waveform and moving it to a highertemperature.

FIG. 5 depicts a treatment module screen that enables a user to provideinstructions as to how many days are to be in a treatment schedule andhow many treatments may be administered per day.

FIG. 6 depicts a treatment module screen that enables a user toauthorize delivery of one or more prescribed thermal waveform(s) duringone or more specified time periods by touching an available treatmentwindow (represented by a grey rectangle with a black dash in its center)and then providing instructions as to which thermal waveform(s) is/areto be delivered during that treatment window (as shown in FIGS. 7-8) andinstructions as to when the treatment window is to begin and end (asshown in FIG. 9).

FIG. 7 depicts a treatment module screen that enables a user to provideinstructions to apply an idealized thermal waveform to the ear canal ofa patient by touching the circular selection indicator to the right ofthe desired waveform.

FIG. 8 depicts a treatment module screen that enables a user to provideinstructions to apply the selected thermal waveform to the left or rightear canal of a patient by touching the upper or lower graph,respectively.

FIG. 9 depicts a treatment module screen that enables a user to provideinstructions as to when a given treatment window is to begin and end(i.e., to provide instructions as to the window of time in which one ormore prescribed thermal waveforms may be administered to a patient).

FIG. 10 depicts a treatment module screen that enables a user to modifya treatment schedule by editing and/or copying previously establishedtreatment sessions (e.g., by changing which thermal waveform(s) are tobe delivered during a given treatment session (as shown in FIGS. 7-8),by changing the start and/or end time for one or more treatment sessions(as shown in FIG. 9), by deleting one or more treatment sessions, etc.).

FIG. 11 depicts a control module screen wherein a thermal waveformdelivered to the left ear canal and a thermal waveform being deliveredto the right ear canal of a patient are graphically represented, withthe current progress of each waveform represented by the changing of thedepicted waveform from light gray to dark grey (i.e., the elapsed timeis represented by the dark gray portion of each waveform and the timeremaining is represented by the light gray portion of each waveform),and wherein the user may stop the treatment session by touching the “X”in the lower left-hand corner of the screen.

FIG. 12 depicts a password protection screen.

FIG. 13 is a block diagram of a controller according to some embodimentsof the present invention.

FIG. 14 is a block diagram of a controller according to some embodimentsof the present invention.

FIG. 15 is a block diagram of a controller according to some embodimentsof the present invention.

FIG. 16 is an illustration of a controller according to some embodimentsof the present invention.

FIG. 17 is an illustration of a controller according to some embodimentsof the present invention.

FIG. 18A is a perspective view of an earpiece according to someembodiments of the present invention.

FIG. 18B is a side view of an earpiece according to some embodiments ofthe present invention.

FIG. 18C is a cross-sectional view of an earpiece according to someembodiments of the present invention.

FIG. 19 is a perspective view of a vestibular stimulation deviceaccording to some embodiments of the present invention.

FIG. 20 is an exploded view of a vestibular stimulation device headsethousing according to some embodiments of the present invention.

FIG. 21A is an exploded, perspective view of an earpiece, a TED and aheat sink according to some embodiments of the present invention.

FIG. 21B is an exploded, cross-sectional view of an earpiece, a TED, aspacer and a heat sink according to some embodiments of the presentinvention.

FIG. 22. Example first and second waveform stimuli.

FIG. 23. A schematic diagram of the horizontal semicircular canals (SCC)that is being heated on one side (wavy lines) and cooled on the other(cross-hatched), where the cupula is shown in dark grey and the arrowsrepresents endolymph flow.

FIG. 24. A schematic diagram of a hierarchical flow of activities aroundthe initiation and continuation of caloric vestibular stimulation (CVS).

FIG. 25. A schematic diagram of physician monitoring and titration ofcaloric vestibular stimulation.

FIG. 26. A schematic diagram of various non-limiting examples ofwaveform stimuli that may be used to carry out the present invention.While each line A through E illustrates several cycles of a givenfrequency and waveform shape, note that “waveform” herein generallyrefers to a single cycle of a given frequency and waveform shape.

FIG. 27. Single square waveform (20° C.) over 7.5 minutes.

FIG. 28. Two consecutive sawtooth waveforms (amplitude of 20° C.) over atime of 10 minutes.

FIG. 29. Sawtooth waveforms for treatment of a chronic migraine patient.

FIG. 30. Pain scores reported by the patient treated with the sawtoothwaveforms of FIG. 31.

FIG. 31. Sawtooth waveforms for treatment of a migraine patient.

FIG. 32. Serum glucose readings for a diabetic patient treated with asawtooth waveform.

FIG. 33. Additional serum glucose readings for a diabetic patienttreated with a sawtooth waveform.

FIG. 34. Cooling sawtooth waveform for treatment of patient withdiabetes and cluster headaches.

FIG. 35. Heating sawtooth waveform for treatment of patient withdiabetes and cluster headaches.

FIG. 36. Segments of the time series of nystagmus are shown byelectronystagmography in FIG. 36A (early segment) and FIG. 36B (latesegment), demonstrating the existence of nystagmus both early in a 12minute period and near the end of the 12 minute period.

FIG. 37. The CVS waveform used for rat #9 (the same waveform was usedfor left ear CVS)

FIG. 38. Raw data from rat #9 showing both the periods of right ear andleft ear CVS induction.

FIG. 39. Raw data showing oscillations in rCBF in the right parietalregion during left ear CVS

FIG. 40. Nearest neighbor averaging of a sequence of oscillations inrCBF during right ear CVS.

FIG. 41. Regional cerebral blood pressure and blood flow for a controlrun in which a caloric vestibular stimulation device was placed on a ratbut not activated.

FIG. 42. Dual ear waveform stimulation of a rat, in which the samewaveform was applied simultaneously to each ear.

FIG. 43. Regional cerebral blood pressure and blood flow for a rattreated with the waveform of FIG. 42.

FIG. 44. Dual ear waveform stimulation of a rat, in which differentwaveforms were applied simultaneously to each ear.

FIG. 45. Regional cerebral blood pressure and blood flow for a rattreated with the waveforms of FIG. 44.

FIG. 46. Electroencephalograph (EEG) spectra of a rat treated with asingle ear, sawtooth waveform, caloric vestibular stimulation. A zero to12 Hz plot is above; a zero to 40 Hz plot is below.

FIG. 47. Heart rate variability data for a male subject treated withdual ear sawtooth waveform caloric vestibular stimulation.

FIG. 48. Migraine pain scores (zero least severe; ten most severe) for afemale subject treated with single ear sawtooth waveform caloricvestibular stimulation.

FIG. 49. Pain scores (zero least sever; ten most severe) for a femalesubject suffering from peripheral neuropathy treated with single ear anddual ear sawtooth waveform caloric vestibular stimulation.

FIG. 50. Serum glucose levels for a male subject afflicted with type IIdiabetes and treated with dual ear caloric vestibular stimulation.

FIG. 51. Sawtooth CVS waveform administered to a representativepediatric epilepsy subject.

FIG. 52. Average number of spikes per minute for four pediatric epilepsysubjects treated with caloric vestibular stimulation as in FIG. 51,before and after stimulation.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The present invention will now be described more fully hereinafter. Thisinvention may, however, be embodied in different forms and should not beconstrued as limited to the embodiments set forth herein. Rather, theseembodiments are provided so that this disclosure will be thorough andcomplete, and will fully convey the scope of the invention to thoseskilled in the art.

The terminology used in the description of the invention herein is forthe purpose of describing particular embodiments only and is notintended to be limiting of the invention. As used in the description ofthe invention and the appended claims, the singular forms “a”, “an” and“the” are intended to include the plural forms as well, unless thecontext clearly indicates otherwise.

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the present applicationand relevant art and should not be interpreted in an idealized or overlyformal sense unless expressly so defined herein. The terminology used inthe description of the invention herein is for the purpose of describingparticular embodiments only and is not intended to be limiting of theinvention. All publications, patent applications, patents and otherreferences mentioned herein are incorporated by reference in theirentirety.

Also as used herein, “and/or” refers to and encompasses any and allpossible combinations of one or more of the associated listed items, aswell as the lack of combinations when interpreted in the alternative(“or”).

Unless the context indicates otherwise, it is specifically intended thatthe various features of the invention described herein can be used inany combination.

Moreover, the present invention also contemplates that in someembodiments of the invention, any feature or combination of features setforth herein can be excluded or omitted. To illustrate, if thespecification states that a complex comprises components A, B and C, itis specifically intended that any of A, B or C, or a combinationthereof, can be omitted and disclaimed.

“About,” as used herein when referring to a measurable value such as anamount or concentration (e.g., the weight percent of the active compoundin the composition) and the like, is meant to encompass variations of20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount.

In describing the invention, it will be understood that a number oftechniques and steps are disclosed. Each of these has individual benefitand each can also be used in conjunction with one or more, or in somecases all, of the other disclosed techniques. Accordingly, for the sakeof clarity, this description will refrain from repeating every possiblecombination of the individual steps in an unnecessary fashion.Nevertheless, the specification and claims should be read with theunderstanding that such combinations are entirely within the scope ofthe invention and the claims.

The present invention may be embodied as systems, methods, and/orcomputer program products. Accordingly, the present invention may beembodied in hardware and/or in software (including firmware, residentsoftware, micro-code, etc.). Furthermore, the present invention may takethe form of a computer program product on a computer-usable orcomputer-readable storage medium having computer-usable orcomputer-readable program code embodied in the medium for use by or inconnection with an instruction execution system. In the context of thisdocument, a computer-usable or computer-readable medium may be anymedium that can contain, store, communicate, propagate, or transport theprogram for use by or in connection with the instruction executionsystem, apparatus, or device.

The computer-usable or computer-readable medium may be, for example butnot limited to, an electronic, magnetic, electromagnetic, infrared, orsemiconductor system, apparatus, or device. More specific examples (anonexhaustive list) of the computer-readable medium would include thefollowing: an electrical connection having one or more wires, a portablecomputer diskette, a random access memory (RAM), a read-only memory(ROM), an erasable programmable read-only memory (EPROM or Flash memory,such as an SD card), and a portable compact disc read-only memory(CD-ROM).

The present invention may be described below with reference to blockdiagrams and/or flowchart illustrations of devices, methods and computerprogram products according to embodiments of the invention. It is to beunderstood that the functions/acts noted in the blocks may occur out ofthe order noted in the operational illustrations. For example, twoblocks shown in succession may in fact be executed substantiallyconcurrently or the blocks may sometimes be executed in the reverseorder, depending upon the functionality/acts involved.

1. Definitions

“Subject” or “patient” as used herein refers generally to human subjectsor patients. The subject or patient may be male or female and may be ofany suitable age, including infant, juvenile, adolescent, adult, andgeriatric subjects. In some embodiments, the present invention may beused to diagnose and/or treat other mammalian subjects such as cats,dogs, monkeys, etc. for medical research or veterinary purposes.

“Concurrently” as used herein means sufficiently close in time toproduce a combined effect. Hence, “concurrently” may be simultaneously,or it may be two or more events occurring within a fixed period of time(e.g., within one, two or three days) or relatively short time periodbefore or after each other.

“Actively controlled waveform” and “actively controlled, time-varyingthermal waveform” as used herein refer to a thermal waveform in whichthe intensity and/or the directionality of the activation signal used todeliver the thermal waveform and/or the temperature of the earpiece usedto deliver the thermal waveform is repeatedly adjusted (e.g.,continuously adjusted or substantially continuously adjusted) duringdelivery of the thermal waveform. For example, the activation signaldriving the TED(s) used to deliver the thermal waveform may becontinuously adjusted in response to feedback data from one or moresensors (e.g., a temperature sensor configured to sense the temperatureof the earpiece with which the TED(s) is/are associated). Such activecontrol may be used to minimize errors in the delivery of a prescribedthermal waveform (e.g., by minimizing thermal drift, which may otherwiseallow the patient's body temperature to adversely affect the accuracy).

“Treatment,” “treat,” and “treating” refer to reversing, alleviating,reducing the severity of, delaying the onset of, inhibiting the progressof, or preventing a disease or disorder as described herein, or at leastone symptom of a disease or disorder as described herein (e.g., treatingone or more of tremors, bradykinesia, rigidity or postural instabilityassociated with Parkinson's disease; treating one or more of intrusivesymptoms (e.g., dissociative states, flashbacks, intrusive emotions,intrusive memories, nightmares, and night terrors), avoidant symptoms(e.g., avoiding emotions, avoiding relationships, avoidingresponsibility for others, avoiding situations reminiscent of thetraumatic event), hyperarousal symptoms (e.g., exaggerated startlereaction, explosive outbursts, extreme vigilance, irritability, panicsymptoms, sleep disturbance) associated with post-traumatic stressdisorder). In some embodiments, treatment may be administered after oneor more symptoms have developed. In other embodiments, treatment may beadministered in the absence of symptoms. For example, treatment may beadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment may also be continued aftersymptoms have resolved—for example, to prevent or delay theirrecurrence. Treatment is not limited to addressing a deficiency and maycomprise providing neuroprotection, enhancing an existing attribute orpositive attribute such as cognition and/or increasing cognitivereserve. Treatment may be as an adjuvant treatment as further describedherein.

“Chronic treatment,” “chronically treating” or the like refer to atherapeutic treatment carried out at least once per week (e.g., two orthree times per week, daily, etc.) over an extended period of time.Chronic treatment typically lasts at least one to two weeks (and, insome embodiments, at least one to two months), but may last as long asrequired to achieve and/or maintain therapeutic efficacy for theparticular condition or disorder for which the treatment is carried out(i.e., the device may be used periodically throughout the patient'slife).

“Adjuvant treatment” as used herein refers to a treatment session inwhich the delivery of one or more thermal waveforms to the vestibularsystem and/or the nervous system of a patient modifies the effect(s) ofone or more active agents and/or therapies. For example, the delivery ofone or more thermal waveforms to the vestibular system and/or thenervous system of a patient may enhance the effectiveness of apharmaceutical agent (by restoring the therapeutic efficacy of a drug towhich the patient had previously become habituated, for example).Likewise, the delivery of one or more thermal waveforms to thevestibular system and/or the nervous system of a patient may enhance theeffectiveness of counseling or psychotherapy. In some embodiments,delivery of one or more thermal waveforms to the vestibular systemand/or the nervous system of a patient may reduce or eliminate the needfor one or more active agents and/or therapies. Adjuvant treatments maybe effectuated by delivering one or more thermal waveforms to thevestibular system and/or the nervous system of a patient prior to,currently with and/or after administration of one or more active agentsand/or therapies.

“Titrate” or “titrating” as used herein with respect to caloricvestibular stimulation means that the stimulus is altered betweentreatment sessions to enhance the efficacy of subsequent sessions and/orreduced undesired side effects during subsequent sessions.

“Controller feedback data” as used herein refers to data that istransmitted to the controller by one or more TEDs and/or one or moresensors and is used by the controller to verify the accuracy of thethermal waveform(s) being delivered, to modulate the activation of oneor more TEDs so as to deliver the appropriate thermal waveform(s) and/orto enable the controller to activate safety precautions in the event ofa system failure. For example, controller feedback data may comprisedata associated with the temperature of an earpiece, wherein said datais used to verify that the appropriate temperature is being delivered tothe ear canal of a patient, to enable the controller toincrease/decrease the activation of one or more TEDs to ensure that theappropriate temperature is delivered to the ear canal of a patientand/or to trigger a system shutdown if the temperature of the earpiecesurpasses a certain threshold (e.g., below about 10° C. or above about50° C.). Likewise, controller feedback data may comprise data associatedwith the temperature of a heat sink that is thermally coupled to one ormore TEDs, wherein said data is used to trigger a system shutdown if thetemperature of the heat sink surpasses a certain threshold (e.g., belowabout 5° C. or above about 50° C.).

“Data associated with the delivery of one or more thermal waveforms” asused herein refers to information associated with the delivery of one ormore thermal waveforms and may include, but is not limited to, dataassociated with the target time/temperature parameters of the thermalwaveform(s), the time/temperature parameters of the thermal waveform(s)delivered; the date/time of delivery of the thermal waveform(s), thetemperature of the patient's ear canal(s) at various time points before,during and/or after delivery of the thermal waveform(s); the temperatureof the patient's inner ear(s) at various time points before, duringand/or after delivery of the thermal waveform(s); the fit of theearpiece(s) at various time points before, during and/or after deliveryof the thermal waveform(s); an estimate of the thermal contact betweenthe earpiece(s) and the patient's ear canal(s) at various time pointsbefore, during and/or after delivery of the thermal waveform(s);patient-specific time constants (e.g., a time constant associated withthe transduction of heat from the ear canal to the inner ear); reactiontime (i.e., how long it took for the patient to react to the thermalwaveform(s)); effectiveness of the thermal waveform(s) (e.g., whetherand to what extent symptoms were relieved, whether the thermalwaveform(s) enhanced the effectiveness of another agent/therapy, etc.);stability of the treatment (i.e., how long the effects of the treatmentlasted); instability of the treatment (i.e., which condition(s) and/orsymptom(s) returned and when did it/they return); the presence orabsence of comorbid disorders, injuries and/or diseases; disorder,injury and/or disease modulation(s) and/or other modification(s) thatoccurred as a result of treatment; the cognitive effect(s) of one ormore thermal waveforms; patient compliance (e.g., whether the patientinitiated delivery at the prescribed time, whether the patient completedthe prescribed treatment session, whether the earpiece(s) remainedproperly fitted in the patient's ear canal(s) for the duration of thetreatment session, etc.); the mood of the patient before, during and/orafter his/her treatment session(s) (e.g., videos/images of a patientthat may be used to assess mood); objectives measures of efficacy (e.g.,nystamography data, EEG data, MRI data, heart rate data, blood pressuredata); subjective measures of efficacy (e.g., a patient-reported painscore); blood chemistry data (e.g., blood A1c levels, blood glucoselevels and blood cortisol levels); saliva chemistry data (e.g., salivacortisol levels); urine chemistry data (e.g., urine cortisol levels))and comments the patient made about his/her treatment session(s) (e.g.,comments made to a physician, submitted in response to an automatedsurvey and/or recorded in a treatment diary). In some embodiments, dataassociated with the delivery of one or more thermal waveforms comprisescontroller feedback data, patient feedback data and/or physicianfeedback data. In some embodiments, data associated with the delivery ofone or more thermal waveforms comprises, consists essentially of orconsists of data associated with the precise time/temperature parametersof the thermal waveform(s) delivered to the patient and a subjectivemeasure of efficacy (e.g., a patient-reported pain score).

“Data associated with the fit of the earpiece(s)” may include, but isnot limited to, data associated with the impedance between an earpieceinserted into the ear canal of a patient and an electrode affixed to asecond location on/in said patient's body (e.g., an electrode placed inor adjacent to the patient's other ear canal), data associated with therate at which the ear canal and/or the inner ear cooled in response to acooling stimulus (e.g., data from a temperature sensor, such asthermistor, that monitors how quickly the ear canal and/or the inner earcools in response to a cooling waveform), data associated with the rateat which the ear canal and/or the inner ear warmed in response to awarming stimulus (e.g., data from a temperature sensor, such as athermistor, that monitors how quickly the ear canal and/or the inner earwarms in response to a warming waveform) and patient comments regardingthe subjective fit of the earpiece(s). In some embodiments, dataassociated with the fit of the earpiece(s) comprises, consistsessentially or consists of data associated with the impedance between anearpiece inserted into the right ear canal of a patient and an earpieceinserted into the left ear canal of said patient.

“Idealized thermal waveform” and “idealized waveform” as used hereinrefer to a thermal waveform that has been indicated and/or approved foruse in the treatment of one or more diseases/disorders/injuries and/orfor use in the provision of neuroprotection, enhanced cognition and/orincreased cognitive reserve. For example, a thermal waveform may beindicated for use in the treatment of migraines if it has effectivelytreated migraines in the past or if it belongs to a class of thermalwaveforms that are known to treat migraines. Likewise, a thermalwaveform may be approved for use in the treatment of a given disorder ifit has received regulatory approval (e.g. FDA approval) for such use, orif it belongs to a class of thermal waveforms that have been approvedfor the treatment of that disorder. An idealized thermal waveform may beindicated/approved for use in the treatment of multiplediseases/disorders/injuries.

“Patient information” as used herein refers to data associated with oneor more patients. Patient information may comprise, but is not limitedto, information related to a patient's identity, a patient's cognitiveabilities, a patient's medical history, a patient's current symptoms (ifany), a patient's present diagnosis (if any), a patient's currentprescriptions (if any) and data associated with the delivery of one ormore thermal waveforms to the vestibular system and/or the nervoussystem of a patient.

“Patient feedback data” as used herein refers to data associated withpatient feedback regarding the delivery of one or more thermalwaveforms. Patient feedback data may comprise, but is not limited to, apatient's evaluation of their pain level before, during and/or afterdelivery of the thermal waveform(s) (e.g., patient-reported pain scoresgiven before, during and after a treatment session) and patient comments(e.g., comments regarding a patient's opinion as to the efficacy of agiven waveform or the effect(s) of certain waveform modifications,etc.).

“Physician feedback data” as used herein refers to data associated withphysician feedback regarding the delivery of one or more thermalwaveforms. Physician feedback data may comprise, but is not limited to,patient information from the patient history database of one or morephysician control devices and comments from one or more physicians(e.g., comments regarding a physician's opinion as to the efficacy of agiven waveform or the effect(s) of certain waveform modifications,etc.).

“Prescription” and “prescription protocol” as used herein refer to a setof instructions and/or limitations associated with stimulation of thevestibular system and/or the nervous system of a patient. In someembodiments, a prescription comprises, consists essentially of orconsists of a set of instructions for delivering of one or more thermalwaveforms (e.g., one or more actively controlled, time-varying thermalwaveforms) to the vestibular system and/or the nervous system of apatient (e.g., by warming and/or cooling an earpiece positioned in theear canal of the patient). A prescription may comprise a set ofinstructions for delivering one or more thermal waveforms to the leftvestibular system of a patient (by delivering one or more thermalwaveforms to the left ear canal of the patient) and/or a set ofinstructions for delivering one or more thermal waveforms to the rightvestibular system of a patient (by delivering one or more thermalwaveforms to the left ear canal of the patient) (i.e., one prescriptionmay comprise instructions for stimulating both the right and leftvestibular systems). A prescription may comprise any suitableinstructions and/or limitations, including, but not limited to, theparameters of the waveform(s) to be delivered to the patient, the numberand frequency of treatment sessions (e.g., X treatment sessions over Ytime period), a limitation as to how many treatment sessions may beadministered during a given time period (e.g., no more than X treatmentsessions within Y time period), instructions as to which thermalwaveform(s) will be administered during a given treatment session (andin what order they are to be administered), instructions as to whichvestibular system will receive a given waveform (e.g., right, left orboth) and an expiration date. In some embodiments, a prescriptioncomprises instructions for delivering a placebo (i.e., for fooling apatient into believing one or more thermal waveforms has been deliveredeven though no such deliver has occurred). In some embodiments, theprescription is generated by a physician. Any conventional securitymeans may be provided to prevent unauthorized modification of theprescription (e.g., the prescription may be password protected, withonly the prescribing physician having knowledge of and/or access to thepassword).

“Registry” as used herein refers to a device configured to receive,store and/or transmit data from/to a plurality of vestibular stimulationdevices and/or other registries. In some embodiments, the registry isconfigured to receive, store and/or transmit data from/to one or moredevices located within a specified geographical region (e.g., thenortheastern United States, the southeastern United States, the UnitedStates, North America, Europe, Japan, China, etc.). For example, aregistry may be configured to receive and/or store one or more thermalwaveforms (i.e., to receive/store data associated with the parameters,indications and/or approvals of one or more thermal waveforms) from oneor more vestibular stimulation devices and/or from one or moreregistries located in the United States. Likewise, a registry may beconfigured to transmit data associated with the parameters, indicationsand/or approvals of one or more thermal waveforms to one or morevestibular stimulation devices and/or to one or more registries locatedin the United States.

As discussed further below, an object of certain embodiments of thisinvention is to provide methods and apparatus that allow for theactivation of innate protective systems in the body. Specifically, theability for chronic application (that is, over a period of days, weeks,months or perhaps years) of titrated thermal stimulation of thelateral/horizontal semicircular canal (it should be noted that othercanals and the otolith structures may also be activated to varyingdegrees) so as to enable a wide variety of time-varying movements of thecupula, thus causing a variety of time-varying (excitatory andinhibitory) activations of the hair cells, which then create phasicfiring of the 8th cranial nerve.

2. Apparatus

As noted above, the present invention provides a vestibular stimulationdevice for delivering one or more thermal waveforms to the vestibularsystem and/or the nervous system of a patient. Thus, a caloricvestibular stimulation apparatus capable of delivering waveform stimulusis preferably used to carry out the present invention. Suitable examplesare illustrated in U.S. patent application Ser. No. 12/970,312, filedDec. 16, 2010 (also published as Rogers and Smith, PCT Application WO2011/075573, on Jun. 23, 2011) and U.S. patent application Ser. No.12/970,347, filed Dec. 16, 2010, (also published as Smith and Rogers,PCT Application WO 2011/075574, on Jun. 23, 2011), the disclosures ofwhich are incorporated by reference herein in their entirety

In some embodiments, the vestibular stimulation device is configured todeliver one or more actively controlled, time-varying thermal waveformsto the vestibular system and/or the nervous system of a patient.

In some embodiments, the vestibular stimulation device is configured togenerate a prescription comprising a set of instructions for deliveringone or more thermal waveforms to the vestibular system and/or thenervous system of a patient and to deliver the prescribed thermalwaveform(s) to the vestibular system and/or the nervous system of saidpatient.

In some embodiments, the vestibular stimulation device comprises,consists essentially of or consists of an earpiece, a TED and acontroller, wherein said TED is thermally coupled to said earpiece andwherein said controller is operatively connected to said TED. Thecontroller may be configured to activate said TED to deliver one or morethermal waveforms to the vestibular system and/or the nervous system ofa patient (i.e., to activate the TED such that the earpiece is warmedand/or cooled so as to deliver the thermal waveform(s) to the vestibularsystem and/or the nervous system of the patient). In some embodiments,the controller is configured to generate a prescription comprising a setof instructions for delivering one or more thermal waveforms to thevestibular system and/or the nervous system of a patient and to activatethe TED to deliver the prescribed thermal waveform(s).

In some embodiments, the vestibular stimulation device comprises,consists essentially of or consists of an earpiece, a plurality of TEDsand a controller, wherein each of said plurality of TEDs is thermallycoupled to said earpiece and wherein said controller is operativelyconnected to each of said plurality of TEDs. The controller may beconfigured to selectively and separately activate each of said pluralityof TEDs to deliver one or more thermal waveforms to the vestibularsystem and/or the nervous system of a patient (i.e., to activate one ormore of the TEDs such that the earpiece is warmed and/or cooled so as todeliver the thermal waveform(s) to the vestibular system and/or thenervous system of the patient). In some embodiments, the controller isconfigured to generate a prescription comprising a set of instructionsfor delivering one or more thermal waveforms to the vestibular systemand/or the nervous system of a patient and to activate the TEDs todeliver the prescribed thermal waveform(s).

In some embodiments, the vestibular stimulation device comprises,consists essentially of or consists of a pair of earpieces, a pair ofTEDs and a controller, wherein one earpiece is configured so as to beinsertable into the left ear canal of a patient and the other earpieceis configured so as to be insertable into the right canal of thepatient, wherein one TED is thermally coupled to each earpiece andwherein said controller is operatively connected to each TED. Thecontroller may be configured to selectively and separately activate eachof said TEDs to deliver one or more thermal waveforms to the vestibularsystem and/or the nervous system of the patient. In some embodiments,the controller is configured to generate a prescription comprising a setof instructions for delivering one or more thermal waveforms to thevestibular system and/or the nervous system of the patient and toactivate the TEDs to deliver the prescribed thermal waveform(s).

In some embodiments, the vestibular stimulation device comprises,consists essentially of or consists of a pair of earpieces, a pluralityof TEDs and a controller, wherein one earpiece is configured so as to beinsertable into the left ear canal of a patient and the other earpieceis configured so as to be insertable into the right canal of thepatient, wherein at least one of said plurality of TEDs is thermallycoupled to each earpiece and wherein said controller is operativelyconnected to each TED. The controller may be configured to selectivelyand separately activate each of said TEDs to deliver one or more thermalwaveforms to the vestibular system and/or the nervous system of thepatient. In some embodiments, the controller is configured to generate aprescription comprising a set of instructions for delivering one or morethermal waveforms to the vestibular system and/or the nervous system ofthe patient and to activate the TEDs to deliver the prescribed thermalwaveform(s).

The vestibular stimulation device may comprise one or more heat sinks.In some embodiments, at least one heat sink is thermally coupled to eachearpiece. In some embodiments, each TED thermally coupled to an earpieceis thermally coupled between the earpiece and at least one heat sink.

The vestibular stimulation device may comprise one or more sensors. Insome embodiments, the sensor(s) is/are configured to provide feedbackdata to the controller. In some such embodiments, the controller isconfigured (e.g., with computer instructions (i.e., software)) to adjustone or more attributes of TED activation (e.g., magnitude, duration,wave pattern, etc.) in response to feedback data received from thesensor(s) with which it is associated. For example, the vestibularstimulation device may be configured such that, during delivery of athermal waveform, the controller activates the TED(s) in a continuous orsubstantially continuous manner and repeatedly, continuously orsubstantially continuously adjusts one or more attributes of TEDactivation in response to feedback data received from one or moresensors (e.g., a temperature sensor configured to provide feedback dataassociated with the temperature of the ear canal of a patient).

The vestibular stimulation device may comprise a headband. In someembodiments, the headband is configured to position the earpiece(s) inthe ear canal(s) of a patient.

As shown in FIG. 1, in some embodiments, the vestibular stimulationdevice 1 comprises a controller 11, a pair of earpieces 12 a, 12 b, apair of TEDs 13 a, 13 b and a pair of heat sinks 15 a, 15 b, wherein oneTED 13 a is thermally connected between one heat sink 15 a and anearpiece 12 a that is configured so as to be insertable into the leftear canal of a patient, wherein the other TED 13 b is thermallyconnected between the a heat sink 15 b and an earpiece 12 b that isconfigured so as to be insertable into the right ear canal of a patientand wherein the controller 11 is operatively connected to each of theTEDs 13 a, 13 b by a thermal stimulation conductive line 16 a, 16 b. Insome such embodiments, each earpiece 12 a, 12 b is operatively connectedto a sensor 14 a, 14 b (e.g., each earpiece may be thermally connectedto a temperature sensor that is configured to detect the temperature ofthe earpiece), and each of the sensors 14 a, 14 b is operativelyconnected to the controller 11 by a wireless connection 17 a, 17 b(using a radiofrequency transceiver or a Bluetooth connection, forexample).

A. Controller

Any suitable controller can be used to carry out the present invention,including, but not limited to, those described in U.S. PatentPublication Nos. 2010/0198204 and 2010/0198282; in U.S. patentapplication Ser. No. 12/970,312 and Ser. No. 12/970,347 and in U.S.Provisional Application Nos. 61/497,761, the disclosure of each of whichis incorporated herein by reference in its entirety.

The controller may be configured to activate at least one TED. In someembodiments, the controller is configured to activate at least one TEDto deliver one or more thermal waveforms to the vestibular system and/orthe nervous system of a patient (e.g., by heating and/or cooling theearpiece(s) that is/are thermally coupled to the TED. For example, thecontroller may be configured to activate the TED(s) based upon aprescription comprising a set of instructions for delivering one or morethermal waveforms to the vestibular system and/or the nervous system ofa patient (i.e., the controller may be configured to activate the TED(s)so as to deliver the prescribed thermal waveform(s) to the vestibularsystem and/or the nervous system of the patient).

The controller may be configured to selectively and separately activatea plurality of TEDs. For example, the controller may be configured toselectively and separately activate the TED(s) thermally coupled to anearpiece inserted into the left ear canal of a patient and the TED(s)thermally coupled to an earpiece inserted into the right ear canal of apatient (e.g., to deliver a thermal waveform only to the left ear canalof the patient, to deliver a thermal waveform only to right ear canal ofthe patient or to simultaneously deliver different thermal waveforms tothe left and right ear canals of the patient). Likewise, the controllermay be configured to separately activate a plurality of TEDs thermallycoupled to a single earpiece.

The controller may be configured to activate the TED(s) in any suitablemanner, including, but not limited to, activation with direct currentand/or electrical pulses. In some embodiments, the controller isconfigured to activate the TED(s) in a continuous or substantiallycontinuous manner, adjusting one or more parameters of TED activation(e.g., magnitude, duration, pulse width, etc.) to deliver the desiredthermal stimulus. For example, the controller may be configured suchthat it continuously or substantially continuously activates each of theTEDs with which it is operatively connected and delivers differentthermal stimuli by modulating the type and/or level of activationapplied to each TED.

The controller may be configured to activate the TED(s) to deliver anysuitable thermal waveform or combination of thermal waveforms,including, but not limited to, those described in U.S. ProvisionalPatent Application Nos. 61/424,132, 61/498,096, 61/424,326, 61/498,080,61/498,911 and 61/498,943, the disclosure of each of which isincorporated herein by reference in its entirety. In some embodiments,the controller is configured to activate the TED(s) to deliver one ormore actively controlled, time-varying thermal waveforms to thevestibular system and/or the nervous system of a patient.

The controller may also be configured to activate the TED(s) to delivera constant thermal stimulus to the ear canal(s) of a patient. Forexample, the controller may be configured to activate the TED(s) so asto maintain the temperature of a patient's ear canal at a targettemperature (e.g., to hold a patient's right canal at 20° C. while athermal waveform is delivered to the patient's left canal).

The controller may likewise be configured to deliver one or more placebowaveforms (i.e., to fool a patient into believing one or more thermalwaveforms has been delivered even though no such delivery has occurred).

In some embodiments, the controller is operatively connected to at leastone TED via a thermal stimulation conductive line. In those embodimentswherein the controller is operatively connected to a plurality of TEDs,the controller may be operatively connected to each TED via a separatethermal stimulation conductive line. In some such embodiments, each ofthe plurality of separate thermal stimulation conductive lines isbundled together into one or more thermal stimulation leads (e.g., thethermal stimulation conductive lines connected to the TED(s) thermallycoupled to the right earpiece may be bundled separately from the thermalstimulation conductive lines connected to the TED(s) thermally coupledto the left earpiece). In some such embodiments, each thermalstimulation lead is connected to the controller via a lead interface(e.g., one or more thermal stimulation leads may be connected to thecontroller using an 18-pin connector).

In some embodiments, the controller is operatively connected to at leastone TED via a wireless connection (using a radiofrequency transceiver ora Bluetooth connection, for example).

The controller may be configured to receive and/or transmit any suitabledata, including, but not limited to, data associated with theparameters, indications and/or approvals of one or more thermalwaveforms, data associated with one or more prescriptions, controllerfeedback data, data associated with the delivery of one or more thermalwaveforms, data associated with the fit of one or more earpieces,physician feedback data and/or patient information.

The controller may be configured to receive and/or transmit data from/tovarious devices, including, but not limited to, a registry (e.g., aregistry comprising data received and/or retrieved from a plurality ofvestibular stimulation devices), a TED, a sensor and/or a portablememory device (e.g., an SD memory card). In some embodiments, thecontroller is configured to receive data associated with the parameters,indications and/or approvals of one or more thermal waveforms (e.g.,idealized thermal waveforms) from a registry and/or a portable memorydevice (e.g., an SD memory card); to receive one or more prescriptionsfrom a registry and/or a portable memory device (e.g., an SD memorycard); to receive controller feedback data from one or more TEDs and/orone or more sensors; to receive data associated with the delivery of oneor more thermal waveforms (e.g., idealized thermal waveforms) from oneor more TEDs and/or one or more sensors; to transmit data associatedwith the delivery of one or more thermal waveforms (e.g., idealizedthermal waveforms) to a registry and/or a portable memory device (e.g.,an SD memory card); to transmit patient feedback data to a registryand/or a portable memory device (e.g., an SD memory card) and/or totransmit patient information to a registry and/or a portable memorydevice (e.g., an SD memory card).

The controller may be configured to receive and/or transmit data overany suitable wired or wireless communications channel, including, butnot limited to, a LAN, the Internet, a public telephone switchingnetwork, Bluetooth, WLAN and the like.

In some embodiments, the controller comprises memory, a processor and apower supply. As will be appreciated by one of skill in the art, theprocessor may be any commercially available or custom microprocessor.Memory can include, but is not limited to, the following types ofdevices: cache, ROM, PROM, EPROM, EEPROM, flash memory, SRAM and DRAM.The power supply may be an internal power supply (e.g., one or morerechargeable batteries that may be recharged without first being removedfrom the controller).

The controller's memory may comprise any suitable software and/or data,including, but not limited to, an operating system, applications, dataand input/output (I/O) drivers.

As will be appreciated by one of skill in the art, the controller mayuse any suitable operating system, including, but not limited to, OS/2,AIX, OS/390 or System390 from International Business Machines Corp.(Armonk, N.Y.), Window CE, Windows NT, Windows95, Windows98,Windows2000, Windows 7 or Windows Vista from Microsoft Corp. (Redmond,Wash.), Mac OS from Apple, Inc. (Cupertino, Calif.), Unix, Linux orAndroid.

As will be appreciated by one of skill in the art, the controller maycomprise any suitable application, including, but not limited to, one ormore programs configured to implement one or more of the variousfeatures of the present invention. For example, the controller maycomprise a waveform module that enables a user to generate and/or modifythe parameters, indications and/or approvals of one or more thermalwaveforms; a treatment module that enables a user to generate, modify,update and/or extend a prescription comprising a set of instructions fordelivering one or more thermal waveforms to the vestibular system and/orthe nervous system of a patient; a control module configured to activateone or more TEDs; a network module configured to receive and/or transmitdata; a GUI module configured to display information and/or accept userinput; a feedback module configured to receive, transmit, and/or analyzecontroller feedback data, data associated with the delivery of one ormore thermal waveforms, data associated with the fit of one or moreearpieces, physician feedback data and/or patient information; an alertgeneration module configured to generate one or more alert messages; atone generation module configured to produce one or more audible tones;a visual indicator module configured to produce one or more visualindicators; an impedance module configured to detect and/or monitor theimpedance between an earpiece inserted into the ear canal of a patientand an electrode affixed to a second location on/in said patient's body,a security module configured to prevent unauthorized use of thecontroller and/or a safety module configured to deactivate thecontroller in the event of a system malfunction and/or failure. In someembodiments, two or more of the aforementioned modules are combined toform a single module configured to carry out the function(s) of each ofthe individual modules (e.g., the controller may comprise awaveform-treatment module that enables a user to generate and/or modifyone or more thermal waveforms and to generate, modify, update and/orextend a prescription). In some embodiments, one of the aforementionedmodules is split into two or more distinct modules (e.g., the controllermay comprise a waveform generation module that enables a user togenerate the parameters, indications and/or approvals of one or morethermal waveforms and a waveform update module that enables a user tomodify the parameters, indications and/or approvals of one or morethermal waveforms). In some embodiments, one or more of the functionsdescribed below with respect to one of the modules described below isperformed by one of the other modules described below (e.g., the controlmodule, rather than the feedback module, may be configured toreceive/analyze controller feedback data).

Waveform Module.

In some embodiments, the controller comprises a waveform module wherebya user may generate and/or modify the parameters, indications and/orapprovals of one or more thermal waveforms.

In some embodiments, the waveform module comprises software that enablesa user to generate and/or modify the parameters of one or more thermalwaveforms by point-to-point design and/or by utilizing mathematicalfunctions. For example, the waveform module may comprise software thatenables a user to generate and/or modify the parameters, indicationsand/or approvals of a thermal waveform by selecting/altering one or moreparameters, including, but not limited to, shape, frequency, amplitudeand duration. In some embodiments, the waveform module enables a user toretrieve/select a thermal waveform from a database and then modify theparameters of that thermal waveform to generate a new thermal waveform.

In some embodiments, the waveform module comprises software that enablesa user to generate and/or modify the parameters, indications and/orapprovals of one or more thermal waveforms using an interactive touchscreen. For example, the waveform module may comprise software thatenables a user to generate the parameters of a thermal waveform bydrawing the desired waveform on an interactive touch screen (FIG. 3).Similarly, the waveform module may enable a user to modify theparameters of a thermal waveform by highlighting one or more points onthe waveform and moving the point(s) to a new location (e.g., ahigher/lower temperature) (FIG. 4).

In some embodiments, the waveform module comprises software thatautomatically adjusts the parameters of the thermal waveform(s) createdby a user to account for system limitations. For example, the waveformmodule may comprise software that automatically adjusts the slope of athermal waveform in accordance with the minimum/maximum temperatureand/or the rate of temperature change that is achievable using aparticular combination of earpiece(s), TED(s), etc. That is, thewaveform module may comprise software that prevents a user fromgenerating parameters for a thermal waveform that cannot be deliveredbecause of system limitations.

In some embodiments, the waveform module comprises software that enablesa user to protect one or more thermal waveforms (i.e., to prevent one ormore users from modifying the parameters, indications and/or approvalsof the thermal waveform(s) and/or from deleting the thermal waveform(s)from a waveform database). For example, the waveform module may comprisesoftware that enables a user to protect one or more idealized thermalwaveforms (e.g., by requiring users to enter a specified password priorto modifying and/or deleting the idealized thermal waveform(s)).

In some embodiments, the waveform module comprises software that enablesa user to remove the protected status from one or more thermalwaveforms. For example, the waveform module may comprise software thatenables a user to remove the protected status from one or more idealizedthermal waveforms (e.g., by entering the appropriate password).

In some embodiments, the waveform module is configured to automaticallygenerate and/or modify the parameters, indications and/or approvals ofone or more thermal waveforms (e.g., idealized thermal waveforms) inresponse to data received from one or more devices/modules. For example,the waveform module may be configured to automatically update one ormore thermal waveforms responsive to data received from one or more TEDsand/or one or more sensors.

The waveform module may be configured to retrieve the parameters,indications and/or approvals of one or more thermal waveforms from anysuitable database, including, but not limited to, a waveform databaseresiding in the controller, a waveform database residing in a registryand/or a waveform database residing in a portable memory device (e.g.,an SD memory card).

Waveform parameters, indications and/or approvals generated and/ormodified by the waveform module may be stored in a database. In someembodiments, the generated/modified parameters, indications and/orapprovals are stored in a waveform database comprising data associatedwith the parameters, indications and/or approvals of one or more thermalwaveforms (e.g., idealized thermal waveforms). For example, thegenerated/modified waveform parameters, indications and/or approvals maybe stored in a waveform database residing in the controller, a waveformdatabase residing in a registry and/or a waveform database residing in aportable memory device (e.g., an SD memory card).

Treatment Module.

In some embodiments, the controller comprises a treatment module wherebya user (e.g., a physician) may generate, modify, update and/or extend aprescription. For example, the treatment module may enable a user togenerate, modify, update and/or extend a prescription comprising a setof instructions for delivering one or more thermal waveforms to thevestibular system and/or the nervous system of a patient.

In some embodiments, the treatment module comprises software thatenables a user to select one or more thermal waveforms from a database(e.g., an idealized thermal waveform from an idealized waveformdatabase) and to provide instructions as to when/how each of thosewaveforms should be administered. For example, a treatment module maycomprise software that enables a user to provide instructions as to howlong a treatment schedule is to last (FIG. 5), to provide instructionsas to how many treatments may be administered each day (FIG. 5), toprovide instructions as to how often each thermal waveform is to beadministered (FIG. 6), to provide instructions as to what time(s) of dayeach thermal waveform is to be administered (FIGS. 6 and 9), to selectone or more idealized thermal waveforms from a database (FIG. 7), toprovide instructions regarding whether each of the selected thermalwaveforms is to be delivered to the right and/or left ear canal of apatient (FIG. 8), etc.

In some embodiments, the treatment module comprises software thatenables a user to modify, update and/or extend a prescription bychanging one or more parameters of the prescription (FIG. 10),including, but not limited to, which thermal waveform(s) are delivered,frequency with which the thermal waveform(s) is/are delivered, and theexpiration date of the prescription. Any suitable prescription may bemodified, updated and/or extended, including, but not limited to,prescriptions stored in a prescription database (e.g., a prescriptiondatabase residing in the controller, in a patient control device, in aphysician control device, in a physician support device, in a registryor in a portable memory device, such as a portable SD memory card).

The treatment module may be configured to retrieve/select thermalwaveforms from any suitable database, including, but not limited to, awaveform database residing in the controller, a waveform databaseresiding in a patient control device, a waveform database residing in aphysician control device, a waveform database residing in a physiciansupport device, a waveform database residing in a registry and/or awaveform database residing in a portable memory device (e.g., an SDmemory card).

The treatment module may be configured to retrieve prescriptions fromany suitable database, including, but not limited to, a prescriptiondatabase residing in the controller, a prescription database residing ina registry and/or a prescription database residing in a portable memorydevice (e.g., an SD memory card).

Prescriptions generated, modified, updated and/or extended by thetreatment module may be added to a database comprising one or moreprescriptions. For example, the prescriptions may be stored in aprescription database residing in the controller, a prescriptiondatabase residing in a registry and/or a prescription database residingin a portable memory device.

Control Module.

In some embodiments, the controller comprises a control moduleconfigured to activate at least one TED (i.e., to control the magnitude,duration, waveform and other attributes of stimulation delivered by theat least one TED). The control module may be configured to activate theTED(s) to deliver any suitable thermal waveform or combination ofthermal waveforms, including, but not limited to, those described inU.S. Provisional Patent Application Nos. 61/424,132, 61/498,096,61/424,326, 61/498,080, 61/498,911 and 61/498,943, the disclosure ofeach of which is incorporated herein by reference in its entirety.

In some embodiments, the control module is configured to selectively andseparately activate a plurality of TEDs (e.g., by activating only one ofsaid plurality of TEDs, by heating one TED and cooling another, bysequentially activating the TEDs, by activating different TEDs usingdifferent temperature/timing parameters, combinations of some or all ofthe foregoing, etc.).

In some embodiments, the control module is configured to activate theTED(s) based upon a prescription. For example, the control module may beconfigured to activate one or more TEDs based upon a prescriptioncomprising a set of instructions for delivering one or more thermalwaveforms to the vestibular system and/or the nervous system of apatient.

In some embodiments, the control module is configured to receive and/orretrieve instructions for delivering a thermal waveform from a database.For example, the control may be configured to receive and/or retrieve aprescription comprising a set of instructions for delivering one or morethermal waveforms to the vestibular system and/or the nervous system ofa patient from a prescription database residing in the controller, froma prescription database residing in a registry and/or from aprescription database residing in a portable memory device (e.g., an SDmemory card).

In some embodiments, the control module is configured to adjust one ormore attributes of TED activation (e.g., magnitude, duration, wavepattern, etc.) in response to controller feedback data received from oneor more TEDs and/or one or more sensors. For example, the control modulemay be configured to increase/decrease the magnitude of TED activationin response to controller feedback data indicating that an earpiece thatis thermally coupled to the TED has not yet reached a target temperature(e.g., the control module may be configured to increase the currentflowing through the TED in response to controller feedback dataindicating that the temperature of the earpiece has not yet dropped tothe target temperature in response to a cooling waveform).

Network Module.

In some embodiments, the controller comprises a network moduleconfigured to receive, retrieve and/or transmit data.

The network module may be configured to receive, retrieve and/ortransmit data from/to any suitable device/module/database, including,but not limited to, other modules residing in the controller, databasesresiding in the controller, a registry, a TED, a sensor and a portablememory device (e.g., an SD memory card).

The network module may be configured to receive, retrieve and/ortransmit data over any suitable wired or wireless communicationschannel, including, but not limited to, a LAN, the Internet, a publictelephone switching network, Bluetooth, WLAN and the like.

The network module may be configured to receive, retrieve and/ortransmit any suitable data, including, but not limited to, dataassociated with the parameters, indications and/or approvals of one ormore thermal waveforms, one or more prescriptions, controller feedbackdata, data associated with the delivery of one or more thermalwaveforms, data associated with the fit of one or more earpieces,patient feedback data, physician feedback data and/or patientinformation.

In some embodiments, the network module is configured to receive and/orretrieve data associated with the parameters, indications and/orapprovals of one or more thermal waveforms from a waveformmodule/database residing in the controller, from a registry and/or froma portable memory device.

In some embodiments, the network module is configured to receive and/orretrieve one or more prescriptions from a treatment module residing inthe controller, from a registry and/or from a portable memory device.

In some embodiments, the network module is configured to receive and/orretrieve controller feedback data, data associated with the delivery ofone or more thermal waveforms and/or data associated with the fit of oneor more earpieces from a control module residing in the controller, froman impedance module residing in the controller, from a feedbackmodule/database residing in the controller, from one or more TEDs and/orfrom one or more sensors.

In some embodiments, the network module is configured to receive and/orretrieve patient feedback data, physician feedback data and/or patientinformation from a feedback module/database residing in the controller,from a GUI module residing in the controller, from a patient informationdatabase residing in the controller, from a registry and/or from aportable memory device.

In some embodiments, the network module is configured to transmit dataassociated with the parameters, indications and/or approvals of one ormore thermal waveforms to a waveform module/database residing in thecontroller, to a treatment module residing in the controller, to aregistry and/or a to portable memory device.

In some embodiments, the network module is configured to transmit one ormore prescriptions to a treatment module residing in the controller, toa prescription database residing in the controller, to a registry and/orto a portable memory device.

In some embodiments, the network module is configured to transmitcontroller feedback data, data associated with the delivery of one ormore thermal waveforms and/or data associated with the fit of one ormore earpieces to a control module residing in the controller, to afeedback module/database residing in the controller, to a registryand/or to a portable memory device.

In some embodiments, the network module is configured to transmitpatient feedback data, physician feedback data and/or patientinformation to a feedback module/database residing in the controller, toa patient information database residing in the controller, to a registryand/or to a portable memory device.

In some embodiments, the network module is configured to access adatabase comprising data associated with the parameters, indicationsand/or approvals of one or more thermal waveforms (e.g., idealizedthermal waveforms). For example, the network module maybe configured toaccess a waveform database residing in the controller, a waveformdatabase residing in a registry and/or a waveform database residing in aportable memory device.

In some embodiments, the network module is configured to access adatabase comprising one or more prescriptions. For example, the networkmodule maybe configured to access a prescription database residing inthe controller, a prescription database residing in a registry and/or aprescription database residing in a portable memory device.

In some embodiments, the network module is configured to access adatabase comprising controller feedback data, data associated with thedelivery of one or more thermal waveforms, data associated with the fitof one or more earpieces, patient feedback data and/or physicianfeedback data. For example, the network module maybe configured toaccess a feedback database residing in the controller, a feedbackdatabase residing in a registry and/or a feedback database residing in aportable memory device.

In some embodiments, the network module is configured to access adatabase comprising patient information. For example, the network modulemaybe configured to access a patient information database residing inthe controller, a patient information database residing in a registryand/or a patient information database residing in a portable memorydevice.

Graphical User Interface Module.

In some embodiments, the controller comprises a GUI module configured todisplay information and/or to accept user input. Any suitable GUI may beused, including, but not limited to, a keyboard, a mouse, an LCD displaywith one or more associated entry keys and an interactive touch screen.For example, the GUI may comprise a static pressure touch-sensitivedisplay, a capacitive touch-sensitive display, a resistivetouch-sensitive display, an electrostatic capacity proximity sensor, amagnetic proximity sensor and/or an infrared proximity sensor. See,e.g., U.S. Patent Publication Nos. 2011/0271222, 2011/0273575,2011/0275414 and 2011/0275416.

The GUI module may be configured to display any suitable information,including, but not limited to, data associated with the delivery of oneor more thermal waveforms. For example, the GUI module may be configuredto display the current date and/or time (FIG. 10); the currenttemperature(s) of the earpiece(s) associated with the controller; thecurrent temperature(s) of a patient's ear canal(s); the currenttemperature(s) of a patient's inner ear(s); the current temperature(s)of the heat sink(s) associated with the controller; one or more targettemperatures (FIG. 11); the amount of time that has elapsed since theonset of delivery of one or more thermal waveforms (FIG. 11); the amountof time remaining in the delivery of one or more thermal waveforms (FIG.11); the amount of time that has elapsed since the onset of a treatmentsession; the amount of time remaining in a treatment session; agraphical representation of the thermal waveform being applied (FIG.11); the number of treatment sessions that have been administered for aprescription; the number of treatment sessions remaining in aprescription; the amount of time remaining until a prescription must berenewed/updated; the amount of remaining battery life, an alert message(e.g., a reminder to a patient that he/she is due for a treatmentsession); the target time/temperature parameters of one or moreprescribed thermal waveform(s) (FIG. 11); the precise time/temperatureparameters of the thermal waveform(s) delivered to a patient; thedate/time of delivery of the thermal waveform(s) delivered to a patient;the temperature(s) of a patient's ear canal(s) at various time pointsbefore, during and/or after delivery of the thermal waveform(s); thetemperature(s) of a patient's inner ear(s) at various time pointsbefore, during and/or after delivery of the thermal waveform(s); the fitof the earpiece(s) at various time points before, during and/or afterdelivery of the thermal waveform(s); an estimate of the thermal contactbetween the earpiece(s) and the patient's ear canal(s) at various timepoints before, during and/or after delivery of the thermal waveform(s);patient-specific time constants (e.g., a time constant associated withthe transduction of heat from a patient's ear canal to the inner ear);reaction time (i.e., how long it took for a patient to react to one ormore thermal waveforms); the effectiveness of one or more thermalwaveforms (i.e., whether and to what extent symptoms were relieved,whether the thermal waveform(s) enhanced the effectiveness of anotheragent/therapy, etc.); the stability of a treatment (i.e., how long theeffects of the treatment lasted); the instability of a treatment (i.e.,which symptom(s) returned and when did it/they return); the presence orabsence of comorbid disorders, injuries and/or diseases; disorder,injury and/or disease modulation(s) and/or modification(s) that occurredas a result of treatment; the cognitive effect(s) of one or more thermalwaveforms; patient compliance (e.g., whether a patient initiateddelivery at the prescribed time, whether a patient completed theprescribed treatment session, whether the earpiece(s) remained properlyfitted in a patient's ear canal(s) for the duration of the treatmentsession, etc.); the mood of a patient at various time points before,during and/or after delivery of one or more thermal waveforms (e.g.,videos/images of a patient that may be used to assess mood); objectivesmeasures of efficacy (e.g., nystamography data, EEG data, MRI data,heart rate data, blood pressure data); subjective measures of efficacy(e.g., a patient-reported pain score); blood chemistry data (e.g., bloodA1c levels, blood glucose levels and blood cortisol levels); salivachemistry data (e.g., saliva cortisol levels); urine chemistry data(e.g., urine cortisol levels)), comments a patient made about his/hertreatment session(s) (e.g., comments made to a physician, submitted inresponse to an automated survey and/or recorded in a treatment diary);the impedance between an earpiece inserted into the ear canal of apatient and an electrode affixed to a second location on/in saidpatient's body (e.g., an electrode placed in or adjacent to thepatient's other ear canal); the rate at which a patient's inner earcools in response to a cooling stimulus (e.g., data from a temperaturesensor, such as thermistor, that monitors how quickly the inner earcools in response to a cooling waveform); the rate at which a patient'sinner ear warms in response to a warming stimulus (e.g., data from atemperature sensor, such as thermistor, that monitors how quickly theinner ear warms in response to a warming waveform) and/or patientcomments regarding the subjective fit of his/her earpiece(s).

The GUI module may be configured to accept any suitable user input,including, but not limited to, instructions for generating and/ormodifying the parameters, indications and/or approvals of a thermalwaveforms; instructions for generating, modifying, updating and/orextending a prescription; patient feedback, physician feedback and/orpatient information. For example, the GUI module may be configured toaccept a pain score and/or patient comments regarding the effectivenessof a treatment session.

In some embodiments, the GUI module is configured to allow a user toinitiate/stop a treatment session (e.g., by pushing/selecting anemergency shutoff button/icon) (FIG. 11).

Feedback Module.

In some embodiments, the controller comprises a feedback moduleconfigured to receive, transmit and/or analyze data.

The feedback module may be configured to receive and/or transmit datafrom/to any suitable device/module/database, including, but not limitedto, other modules residing in the controller, databases residing in thecontroller, a registry, a TED, a sensor and a portable memory device(e.g., an SD memory card).

The feedback module may be configured to receive and/or transmit dataover any suitable wired or wireless communications channel, including,but not limited to, a LAN, the Internet, a public telephone switchingnetwork, Bluetooth, WLAN and the like.

The feedback module may be configured to receive, transmit and/oranalyze any suitable data, including, but not limited to, controllerfeedback data, data associated with the delivery of one or more thermalwaveforms, data associated with the fit of one or more earpieces,patient feedback data, physician feedback data and/or patientinformation.

In some embodiments, the feedback module is configured to receive and/oranalyze controller feedback data, data associated with the delivery ofone or more thermal waveforms and/or data associated with the fit of oneor more earpieces from an impedance module residing in the controller,from a feedback database residing in the controller, from one or moreTEDs and/or from one or more sensors. For example, the feedback modulemay be configured to analyze the accuracy with which one or moreprescribed waveforms was delivered to a patient, the fit of an earpiecebased upon the rate at which the temperature of the earpiece changes inresponse to a cooling/warming waveform, the slew rate associated withone or more TEDs, the impedance between an earpiece positioned in theleft ear canal of a patient and an earpiece positioned in the right earcanal of a patient, the impedance between an earpiece positioned in theear canal of a patient and an electrode affixed to a second locationon/in the patient's body, etc.

In some embodiments, the feedback module is configured to receive and/oranalyze patient feedback data, physician feedback data and/or patientinformation from a GUI module residing in the controller, from aregistry and/or from a portable memory device. For example, the feedbackmodule may be configured to analyze the effectiveness of a given thermalwaveform or combination of thermal waveforms (e.g., by analyzing painscores entered before, during and after a treatment session), theeffect(s) of one or more waveform modifications (e.g., by analyzingwhether/how much a given waveform modification changed the effectivenessof a thermal waveform in treating a disease/disorder), etc.

In some embodiments, the feedback module is configured to transmitcontroller feedback data, data associated with the delivery of one ormore thermal waveforms, data associated with the fit of one or moreearpieces, patient feedback data, physician feedback data, patientinformation and/or data associated with its analysis to a control moduleresiding in the controller, to a feedback database residing in thecontroller, to a patient information database residing in thecontroller, to a registry and/or to a portable memory device (e.g., anSD memory card).

Alert Generation Module.

In some embodiments, the controller comprises an alert generation moduleconfigured to generate one or more alert messages.

The alert generation module may be configured to generate any suitablealert message, including, but not limited to, a reminder that a patientis due for a treatment session; a reminder that a patient must enterpatient feedback data (e.g., a pain score) following a treatmentsession; an indication of the number of treatment sessions remaining ina prescription; an error message indicating that a treatment session hasbeen interrupted due to a system error; an alert indicating that one ormore idealized thermal waveforms has been modified; an alert indicatingthat a given modification is likely to increase/decrease theeffectiveness of a given thermal waveform and/or an alert indicatingthat a given thermal waveform, class of thermal waveforms or combinationof thermal waveforms has been identified as being indicated and/orapproved for use in the treatment of a disease/disorder; a reminder thata patient must contact his/her physician to update/extend his/herprescription and a warning that the controller's internal power supplyis low.

In some embodiments, the alert generation module is configured tocommunicate with various devices/modules, including, but not limited to,a registry, a TED, a sensor, a portable memory device (e.g., an SDmemory card) and other modules of the controller. For example, the alertgeneration module may be configured to provide instructions to the GUImodule and/or the tone generation module for displaying one or morealert messages and/or for generation an audible tone to alert a user ofthe presence of the one or more alert messages. The graphical userinterface module may be configured to display the one or more alertmessages immediately upon generation or upon interaction with a user(e.g., an alert notification icon may be generated, with the alertmessage being displayed only after the user indicates that he/she wishesto view the message).

Tone Generation Module.

In some embodiments, the controller comprises a tone generation moduleconfigured to produce audible tones. In some such embodiments, the tonegeneration module comprises a piezo buzzer. Audible tones may beproduced to alert a user to various circumstances/events, including, butnot limited to, the start of a treatment session, the end of a treatmentsession, interruption of a treatment session, low battery power and theexistence of an unread/unviewed alert message. Audible tones may begenerated repeatedly in response to a single circumstance/event (e.g.,an audible tone may be generated repeatedly until the user views/readsthe message) and may become progressively louder and/or more frequentwith time.

Visual Indicator Module.

In some embodiments, the controller comprises a visual indicator moduleconfigured to notify a user of the existence of an unread/unviewed alertmessage and/or to notify the user that a treatment session is inprogress. In some such embodiments, the visual indicator modulecomprises an LED indicator light. The visual indicator module may beactivated repeatedly in response to a single alert message (e.g., an LEDlight may be illuminated repeatedly until the user views/reads themessage) or may remain activated until the user views/reads the message.In some preferred embodiments, an LED indicator light may be illuminatedthroughout a treatment session and deactivated upon completion of thetreatment session, and may change color to signal various events withina treatment session (e.g., the light may appear blue during coolingperiods and appear red during heating periods).

Impedance Module.

In some embodiments, the controller comprises an impedance moduleconfigured to detect and/or monitor the impedance and/or capacitancebetween an earpiece inserted into the ear canal of a patient and anelectrode affixed to a second location on/in said patient's body. Forexample, the impedance module may be configured to deliver an electricalcurrent to the earpiece and to measure and/or record the impedanceand/or capacitance between the earpiece and the electrode.

In some embodiments, the impedance module may be configured to detectand/or monitor the impedance and/or capacitance between an earpieceinserted into the right ear canal of a patient and an earpiece insertedinto the left ear canal of said patient. For example, the impedancemodule may be configured to deliver an electrical current to theearpiece inserted into the right ear canal of the patient and to measureand/or record the impedance and/or capacitance between the twoearpieces.

Without wishing to be bound by theory, it is believed that if each ofthe earpieces is in substantially good thermal contact with thepatient's ear canal, then the earpieces will also be in substantiallygood electrical contact with the patient's ear canals, and the patient'shead will substantially complete an electrical circuit between theearpieces. However, if either of the earpieces is not in substantiallygood thermal contact with the patient's ear canal, then there willgenerally be poor electrical contact with the patient's ear canal, andthe patient's head will not complete the electrical circuit between theearpieces and an open circuit will be detected by the impedance module.

The impedance value between an earpiece inserted into the ear canal ofthe patient and the electrode affixed to a second location (e.g., anearpiece inserted into the patient's other ear canal) may be used toestimate the thermal contact between the earpiece(s) and the patient'sear canal(s). In some embodiments, impedance values may be detected fora range of patients to determine a range of impedance values in which itmay be assumed that the earpiece(s) is/are in substantially good thermalcontact with the patient's ear canal(s). When a vestibular stimulationdevice is being fitted to a new patient, the impedance value may bedetected, and if the impedance value is within the acceptable range, itmay be assumed that there is substantially good thermal contact betweenthe earpiece(s) and the patient's ear canal(s). In some embodiments,when a vestibular stimulation device is being fitted to a new patient,the impedance value between the earpiece inserted into the right earcanal of the patient and the earpiece inserted into the left canal ofthe patient may be detected and used as a patient-specific baseline tolater determine whether the patient is using the vestibular stimulationdevice in the proper configuration (i.e., whether the earpieces areproperly fitted into the patient's ear canals during a given treatmentsession).

The impedance module may be configured to monitor the impedance valuebetween an earpiece inserted into the ear canal of a patient and anelectrode affixed to a second location on/in said patient's body (e.g.,between two earpieces), and the impedance values may be analyzed (e.g.,by a medical health professional or the impedance module) to determinewhether the earpiece(s) is/was properly fitted at various times before,during and/or after delivery of the thermal waveform(s). In someembodiments, the impedance module may be configured to provide feedbackto the user if/when the impedance value indicates that the earpiece(s)are not in substantially good thermal contact with the patient's earcanal(s). In this configuration, the impedance module may provide anestimation of a degree of thermal contact between the earpiece(s) andthe patient's ear canal(s) in real-time or in data recorded and analyzedat a later time.

The impedance module may be configured to provide controller feedbackdata to the control module so that the control module may modulate theamplitude of the waveform(s) delivered by the TED(s) responsive to thedegree of thermal contact between the earpiece(s) and the patient's earcanal(s). For example, if the impedance module determines that there isa poor fit and poor thermal contact between the earpiece(s) and the earcanal(s), then the control module may increase the thermal output of theTED(s) to compensate for the poor thermal contact.

Security Module.

In some embodiments, the controller comprises a security moduleconfigured to prevent unauthorized use of the controller (i.e., toprevent unauthorized persons from using the vestibular stimulationdevice, to prevent authorized persons from using the vestibularstimulation device in an unauthorized manner, etc.).

The security module may be configured to prevent unauthorized use of thecontroller using any suitable means of security, including, but notlimited to, password protection and data encryption. For example, thesecurity module may be configured such that a user is required to inputa designated password prior to initializing treatment; generating and/ormodifying a thermal waveform; generating, modifying, updating and/orextending a prescription; entering/viewing patient feedback data;entering/viewing physician feedback data and/or entering/viewing patientinformation (FIG. 12). In some embodiments, prescriptions are providedin an encrypted format, and the security module is configured such thatthe prescriptions can only be decrypted by the vestibular stimulationdevice assigned to or belonging to the patient for whom the prescriptionwas generated. In some embodiments, prescriptions are provided in anencrypted format, and the security module is configured such that theprescriptions can only be decrypted by inputting a designated decryptionkey. In some embodiments, a patient may be required to purchase adecryption key and/or password for each treatment session, prescription,refill, etc.

Safely Module.

In some embodiments, the controller comprises a safety module configuredto deactivate the controller in the event of a system malfunction and/orfailure.

The safety module may be configured to deactivate the controller for anysuitable reason, including, but not limited to, excessive heating and/orcooling of an earpiece, excessive heating and/or cooling of a heat sink,a loss of thermal coupling between an earpiece and the TED(s) with whichit is associated, a loss of thermal coupling between a heat sink and theTED(s) with which it is associated, patient noncompliance (e.g., if thepatient has removed the earpiece(s) during a treatment session) andfaulty signaling from the controller to the associated TED(s).

In some embodiments, the safety module is configured to deactivate thecontroller if/when the temperature of an earpiece surpasses a specifiedsafety threshold. For example, the safety module may be configured todeactivate the controller if/when the temperature of the earpiece dropsbelow about 10° C. and/or rises above about 50° C.

In some embodiments, the safety module is configured to deactivate thecontroller if/when the temperature of a heat sink that is thermallycoupled to an earpiece surpasses a specified safety threshold. Forexample, the safety module may be configured to deactivate thecontroller if/when the temperature of the heat sink drops below about 5°C. and/or rises above about 50° C.

In some embodiments, the safety module is configured to deactivate thecontroller if/when one or more of the activation signals sent from thecontroller to the associated TED(s) indicates that the system is may beoperating outside of a predefined safety range. For example, the safetymodule may be configured to deactivate the controller if/when anactivation signal sent from the controller to an associated TED exceedsthe level of activation that would normally be required to deliver theprescribed thermal waveform in a properly functioning system.

As will be appreciated by one of skill in the art, the controller maycomprise any suitable data, including, but not limited to, static and/ordynamic data used by the operating system, applications, I/O devicedrivers and other software components, controller feedback data, dataassociated with the parameters, indications and/or approvals of one ormore thermal waveforms (e.g., idealized thermal waveforms), dataassociated with one or more prescriptions, data associated with thedelivery of one or more thermal waveforms, data associated with the fitof one or more earpieces, patient feedback data, physician feedback dataand patient information. For example, the controller may comprise awaveform database comprising data associated with the parameters,indications and/or approvals of one or more idealized thermal waveforms;a prescription database comprising data associated with one or moreprescriptions; a feedback database comprising controller feedback data,data associated with the delivery of one or more thermal waveforms tothe vestibular system and/or the nervous system of a patient, patientfeedback data and physician feedback data and/or a patient historydatabase comprising data associated with one or more patients. In someembodiments, two or more of the aforementioned databases are combined toform a single database comprising data from each of the individualdatabases (e.g., the controller may comprise a feedback-history databasecomprising data associated with the delivery of one or more thermalwaveforms and patient information). In some embodiments, one of theaforementioned databases is split into two or more distinct databases(e.g., the controller may comprise a controller feedback databasecomprising controller feedback data, a delivery feedback databasecomprising data associated with the specific parameters of the thermalwaveform(s) delivered to a patient, a patient feedback databasecomprising patient feedback data and a physician feedback databasecomprising physician feedback data). In some embodiments, one or more ofthe data types described below with respect to one of the databasesdescribed below is stored in one of the other databases described below(e.g., the patient information database, rather than the feedbackdatabase, may be configured to receive/store patient feedback data). Insome embodiments, data is transmitted, received and/or stored in acontrolled format (e.g., in a standardized format using forms/programssupplied by a registry). The controller may be configured to transmit,receive and store data in a manner that ensures compliance with any andall applicable laws and/or regulations (e.g., the Health InsurancePortability and Accountability Act of 1996 (P.L. 104-191; “HIPAA”)).

Waveform Database.

In some embodiments, the controller comprises a waveform databaseconfigured to receive, transmit and/or store data associated with theparameters, indications and/or approvals of one or more thermalwaveforms (e.g, one or more idealized thermal waveforms). In some suchembodiments, the waveform database is configured such that one or moreof the thermal waveforms stored therein is/are protected (e.g., usersmay be prevented from modifying and/or deleting the idealized thermalwaveform(s) stored in the waveform database).

The waveform database may comprise any suitable type of memoryincluding, but not limited to, cache, ROM, PROM, EPROM, EEPROM, flashmemory, SRAM and DRAM. In some embodiments, the waveform databasecomprises a portable memory device, such as an SD memory card or a USBmemory stick. For example, the waveform database may comprise an SDmemory card interface and one or more prescriptions may be stored on aportable SD memory card.

The waveform database may be configured to receive and/or transmit datafrom/to any suitable device/module/database, including, but not limitedto, modules residing in the controller, a registry, a TED, a sensor anda portable memory device (e.g., an SD memory card).

The waveform database may be configured to receive and/or transmit dataover any suitable wired or wireless communications channel, including,but not limited to, a LAN, the Internet, a public telephone switchingnetwork, Bluetooth, WLAN and the like.

Prescription Database.

In some embodiments, the controller comprises a prescription databaseconfigured to receive, transmit and/or store one or more prescriptions,wherein each prescription comprising a set of instructions fordelivering one or more thermal waveforms to the vestibular system and/orthe nervous system of a patient.

The prescription database may comprise any suitable type of memoryincluding, but not limited to, cache, ROM, PROM, EPROM, EEPROM, flashmemory, SRAM and DRAM. In some embodiments, the prescription databasecomprises a portable memory device, such as an SD memory card or a USBmemory stick. For example, the prescription database may comprise an SDmemory card interface and one or more prescriptions may be stored on aportable SD memory card.

The prescription database may be configured to receive and/or transmitdata from/to any suitable device/module/database, including, but notlimited to, modules residing in the controller, a registry, a TED, asensor and a portable memory device (e.g., an SD memory card).

The prescription database may be configured to receive and/or transmitdata over any suitable wired or wireless communications channel,including, but not limited to, a LAN, the Internet, a public telephoneswitching network, Bluetooth, WLAN and the like.

Feedback Database.

In some embodiments, the controller comprises a feedback databaseconfigured to receive, transmit and/or store data.

The feedback database may comprise any suitable type of memoryincluding, but not limited to, cache, ROM, PROM, EPROM, EEPROM, flashmemory, SRAM and DRAM. In some embodiments, the feedback databasecomprises a portable memory device, such as an SD memory card or a USBmemory stick. For example, the feedback database may comprise an SDmemory card interface and one or more prescriptions may be stored on aportable SD memory card.

The feedback database may be configured to receive and/or transmit datafrom/to any suitable device/module/database, including, but not limitedto, modules residing in the controller, a registry, a TED, a sensor anda portable memory device (e.g., an SD memory card).

The feedback database may be configured to receive and/or transmit dataover any suitable wired or wireless communications channel, including,but not limited to, a LAN, the Internet, a public telephone switchingnetwork, Bluetooth, WLAN and the like.

The feedback database may be configured to receive/transmit and/or storeany suitable data, including, but not limited to, controller feedbackdata, data associated with the delivery of one or more thermalwaveforms, data associated with the fit of one or more earpieces,patient feedback data, physician feedback data and/or patientinformation. For example, the feedback database may comprise a log filedetailing the target time/temperature parameters of one or moreprescribed thermal waveform(s); the time/temperature parameters of thethermal waveform(s) delivered to a patient; the date/time of delivery ofthe thermal waveform(s) delivered to a patient; the temperature(s) of apatient's ear canal(s) at various time points before, during and/orafter delivery of one or more thermal waveforms; the temperature(s) of apatient's inner ear(s) at various time points before, during and/orafter delivery of one or more thermal waveforms; the fit of one or moreearpieces at various time points before, during and/or after delivery ofone or more thermal waveforms; an estimate of the thermal contactbetween one or more earpieces and a patient's ear canal(s) at varioustime points before, during and/or after delivery of one or more thermalwaveforms; patient-specific time constants (e.g., a time constantassociated with the transduction of heat from a patient's ear canal tothe inner ear); a patient's reaction time (i.e., how long it took for apatient to react to one or more thermal waveforms); effectiveness of oneor more thermal waveforms (i.e., whether and to what extent symptomswere relieved, whether the thermal waveform(s) enhanced theeffectiveness of another agent/therapy, etc.); stability of a treatment(i.e., how long the effects of a treatment lasted); instability of atreatment (i.e., which symptom(s) returned and when did it/they return);the presence or absence of comorbid disorders, injuries and/or diseases;disorder, injury and/or disease modulation(s) and/or modification(s)that occurred as a result of treatment; the cognitive effect(s) of oneor more thermal waveforms; patient compliance (e.g., whether a patientinitiated delivery at the prescribed time, whether a patient completedthe prescribed treatment session, whether the earpiece(s) remainedproperly fitted in a patient's ear canal(s) for the duration of thetreatment session, etc.); the mood of a patient at various time pointsbefore, during and/or after delivery of one or more thermal waveforms(e.g., videos/images of a patient that may be used to assess mood);objectives measures of efficacy (e.g., nystamography data, EEG data, MRIdata, heart rate data, blood pressure data); subjective measures ofefficacy (e.g., a patient-reported pain score); blood chemistry data(e.g., blood A1c levels, blood glucose levels and blood cortisollevels); saliva chemistry data (e.g., saliva cortisol levels); urinechemistry data (e.g., urine cortisol levels)); comments a patient madeabout his/her treatment session(s) (e.g., comments made to a physician,submitted in response to an automated survey and/or recorded in atreatment diary); the impedance between an earpiece inserted into theear canal of a patient and an electrode affixed to a second locationon/in said patient's body (e.g., an electrode placed in or adjacent tothe patient's other ear canal); the rate at which an earpiece is cooledin response to a cooling stimulus (e.g., data from a temperature sensor,such as thermistor, that monitors how quickly the earpiece cools inresponse to a cooling waveform); the rate at which an earpiece is warmedin response to a warming stimulus (e.g., data from a temperature sensor,such as a thermistor, that monitors how quickly the earpiece warms inresponse to a warming waveform); the rate at which a patient's ear canaland/or inner ear cooled in response to a cooling stimulus (e.g., datafrom a temperature sensor, such as thermistor, that monitors how quicklythe ear canal and/or the inner ear cools in response to a coolingwaveform); the rate at which a patient's ear canal and/or inner earwarmed in response to a warming stimulus (e.g., data from a temperaturesensor, such as a thermistor, that monitors how quickly the ear canaland/or the inner ear warms in response to a warming waveform); patientcomments regarding the subjective fit of one or more earpieces;physician comments regarding the effectiveness of one or more thermalwaveforms and/or physician comments regarding the effect(s) of one ormore waveform modifications.

Patient History Database.

In some embodiments, the controller comprises a patient history databaseconfigured to receive, transmit and/or store patient information.

The patient history database may comprise any suitable type of memoryincluding, but not limited to, cache, ROM, PROM, EPROM, EEPROM, flashmemory, SRAM and DRAM. In some embodiments, the patient history databasecomprises a portable memory device, such as an SD memory card or a USBmemory stick. For example, the patient history database may comprise anSD memory card interface and one or more prescriptions may be stored ona portable SD memory card.

The patient history database may be configured to receive and/ortransmit data from/to any suitable device/module/database, including,but not limited to, modules residing in the controller, a registry, aTED, a sensor and a portable memory device (e.g., an SD memory card).

The patient history database may be configured to receive and/ortransmit data over any suitable wired or wireless communicationschannel, including, but not limited to, a LAN, the Internet, a publictelephone switching network, Bluetooth, WLAN and the like.

Patient information may comprise any suitable information that isassociated with a patient, including, but not limited to, the patient'smedical history, the patient's current symptoms (if any), the patient'spresent diagnosis (if any), the patient's current prescriptions (if any)and data associated with the delivery of one or more thermal waveformsto the vestibular system and/or the nervous system of the patient.

As will be appreciated by one of skill in the art, the controller maycomprise any I/O device drivers, including, but not limited to, softwareroutines accessed through the operating system by the applications tocommunicate with devices such as I/O ports, memory components, TEDsand/or sensors.

As will be appreciated by one of skill in the art, the controller may beconfigured (e.g., with computer instructions (i.e., software)) tooperate in a plurality of distinct modes. In each mode, the controllermay be configured to permit access to some modules, databases and/orfunctionalities and to prevent access to other modules, database and/orfunctionalities. For example, the controller may be configured tooperate in a patient mode, wherein the user is allowed to performpatient-oriented tasks, such as starting/stopping a treatment sessionand/or providing feedback regarding the effectiveness of a treatmentsession, but is prevented from accessing othermodules/databases/functionalities (e.g., the user may be preventedgenerating, modifying, updating and/or extending prescriptions).Similarly, the controller may be configured to operate in a physicianmode, wherein the user is allowed to perform physician-oriented tasks,such as generating, modifying, updating and/or extending a prescriptioncomprising a set of instructions for delivering one or more thermalwaveforms to the vestibular system and/or the nervous system of apatient, but is prevented from accessing othermodules/databases/functionalities (e.g., the user may be prevented fromgenerating and/or modifying one or more thermal waveforms). Likewise,the controller may be configured to operate in a researcher mode,wherein the user is allowed to perform researcher-oriented tasks, suchas generating and/or modifying one or more idealized thermal waveforms,but is prevented from accessing other modules/databases/functionalities(e.g., the user may be prevented from modifying the underlyingoperational parameters of the controller). In addition, the controllermay be configured to operate in an engineer mode, wherein the user isallowed to access all of the controller'smodules/databases/functionalities. Each mode may be protected via aunique security measure (e.g., the controller may be configured suchthat each mode is protected by a unique password).

As shown in FIGS. 13-15, in some embodiments of the present invention,the controller 11 comprises memory 110, a processor 111 and a powersupply 112 (e.g., an internal power supply), wherein memory 110 isrepresentative of the overall hierarchy of memory devices containingsoftware and data used to implement the functionality of the controller11 and wherein the processor 111 communicates with the memory 110 via anaddress/data bus 1100. In particular embodiments, memory 110 comprisesan operating system 110 a, applications 110 b (e.g., a waveform module11 a configured to generate and/or modify the parameters, indicationsand/or approvals of one or more thermal waveforms; a treatment module 11b configured to generate, modify, update and/or extend a prescriptioncomprising a set of instructions for delivering one or more thermalwaveforms to the vestibular system and/or the nervous system of apatient; a control module 11 c configured to activate at least one TEDto deliver one or more thermal waveforms to the vestibular system and/orthe nervous system of a patient; a network module 11 d configured toreceive and/or transmit data, a GUI module 11 e configured to displayinformation and/or accept user input and/or a feedback module 11 fconfigured to receive, transmit, and/or analyze data), data 110 c (e.g.,a waveform database 11 h comprising data associated with the parameters,indications and/or approvals of one or more thermal waveforms; aprescription database 11 i comprising at least one prescriptioncomprising a set of instructions for delivering one or more thermalwaveforms to the vestibular system and/or the nervous system of apatient; a feedback database 11 j comprising data associated with thedelivery of one or more thermal waveforms and/or a patient historydatabase 11 k comprising patient information) and I/O drivers 110 d. Insome such embodiments, data 110 c comprises one or more databases storedon a portable memory device. For example, data 110 c may comprise an SDmemory card interface and a portable SD memory card comprising awaveform database 11 h, a prescription database 11 i, a feedbackdatabase 11 j and/or a patient history database 11 k.

In some embodiments, the control module 11 c is configured to activateone or more TEDs to delivery of one or more thermal waveforms to thevestibular system and/or the nervous system of a patient. For example,the control module 11 c may be configured to activate the TED(s) basedupon a prescription stored in the prescription database 11 i. In somesuch embodiments, the prescription is stored on an SD memory cardinserted into an SD memory card interface.

In some embodiments, the network module 11 d is configured to receivedata associated with the parameters, indications and/or approvals of oneor more thermal waveforms from the waveform module 11 a, a registryand/or a portable memory device (e.g., an SD memory card) and totransmit the data to the waveform database 11 h for storage. In somesuch embodiments, the data is stored on an SD memory card inserted intoan SD memory card interface.

In some embodiments, the network module 11 d is configured to retrievedata associated with the parameters, indications and/or approvals of oneor more thermal waveforms from the waveform database 11 h, a registryand/or a portable memory device (e.g., an SD memory card) and totransmit the data to the waveform module 11 a and/or the treatmentmodule 11 b.

In some embodiments, the network module 11 d is configured to receiveone or more prescriptions from the treatment module 11 b, a registryand/or a portable memory device (e.g., an SD memory card) and totransmit the prescription(s) to the prescription database 11 i forstorage. In some such embodiments, the prescription(s) is/are stored onan SD memory card inserted into an SD memory card interface.

In some embodiments, the network module 11 d is configured to retrieveone or more prescriptions from the prescription database 11 i, aregistry and/or a portable memory device (e.g., an SD memory card) andto transmit the prescription(s) to the treatment module 11 b and/or thecontrol module 11 c.

In some embodiments, the network module 11 d is configured to receivecontroller feedback data, data associated with the delivery of one ormore thermal waveforms and/or data associated with the fit of one ormore earpieces from the control module 11 e, one or more TEDs 13 a, 13b, one or more sensors 14 a, 14 b, a registry and/or a portable memorydevice (e.g., an SD memory card) and to transmit that data to thefeedback database 11 j for storage. In some such embodiments, the datais stored on an SD memory card inserted into an SD memory cardinterface.

In some embodiments, the network module 11 d is configured to receivepatient feedback data from the GUI module 11 e and to transmit that datato the feedback database 11 j for storage. In some such embodiments, thepatient information is stored on an SD memory card inserted into an SDmemory card interface.

In some embodiments, the network module 11 d is configured to retrievecontroller feedback data, data associated with the delivery of one ormore thermal waveforms, data associated with the fit of one or moreearpieces and/or patient feedback data from the feedback database 11 jand to transmit the data to the control module 11 e, the feedback module11 f, a registry and/or a portable memory device (e.g., an SD memorycard).

In some embodiments, the network module 11 d is configured to receivepatient feedback data from the GUI module 11 e and to transmit that datato the feedback database 11 j for storage. In some such embodiments, thepatient information is stored on an SD memory card inserted into an SDmemory card interface.

In some embodiments, the network module 11 d is configured to retrievepatient feedback data from the feedback database 11 j and to transmitthe data to the feedback module 11 f, a registry and/or a portablememory device (e.g., an SD memory card).

In some embodiments, the network module 11 d is configured to receivepatient information from the GUI module 11 e, a registry and/or aportable memory device (e.g., an SD memory card) and to transmit thatdata to the patient history database 11 k for storage. In some suchembodiments, the patient information is stored on an SD memory cardinserted into an SD memory card interface.

In some embodiments, the network module 11 d is configured to retrievepatient information from the patient history database 11 k and totransmit the patient information to a registry and/or a portable memorydevice (e.g., an SD memory card).

FIG. 16 is an illustration of a controller of the present invention. Asshown therein, in some embodiments, the controller may comprise agraphical user interface 113 comprising an LCD display 113 a configuredto display data associated with the delivery of one or more thermalwaveforms and a treatment start/stop button 113 b whereby a patient mayinitiate and/or terminate a treatment session, an SD memory cardinterface 114 into which an SD memory card comprising a prescription maybe inserted, an LED indicator light 115 configured to notify a patientof the occurrence of various events (e.g., the start of a treatmentsession or the generation of an alert message), a USB interface 116configured to transmit/receive data and/or to recharge an internal powersupply, a lead interface 117 whereby a patient may operatively connectone or more thermal stimulation leads and an on/off button 118.

FIG. 17 is an illustration of another controller of the presentinvention. As shown therein, in some embodiments, the controller maycomprise a graphical user interface comprising an interactivetouchscreen 113 c, an SD memory card interface 114 into which an SDmemory card may be inserted, a USB interface 116 configured totransmit/receive data and/or to recharge an internal batter supply and alead interface 117 whereby a user may operatively connect one or morethermal stimulation leads.

B. Earpiece.

The vestibular stimulation device may comprise one or more earpieces.Earpieces of the present invention may be configured so as to beinsertable into the left ear canal and/or the right ear canal of apatient.

Any suitable earpiece can be used to carry out the present invention,including, but not limited to, those described in U.S. PatentPublication Nos. 2010/0198204 and 2010/0198282; in U.S. patentapplication Ser. No. 12/970,312 and Ser. No. 12/970,347; in U.S.Provisional Application Nos. 61/497,761; in U.S. Design Pat. No.D645,455, the disclosure of each of which is incorporated herein byreference in its entirety.

Earpieces of the present invention may comprise any suitable material,including, but not limited to, a rigid, thermally conductive material(e.g., a metal or a metal alloy). For example, the earpiece(s) maycomprise aluminum or an aluminum alloy (e.g., 6061 aluminum).

Earpieces of the present invention may be of any suitable size/shape. Insome embodiments, the earpiece(s) comprise(s) a distal end configured soas to be insertable into the left ear canal and/or the right ear canalof a patient and a proximal end configured so as to be thermallyconnected to one or more TEDs. In some embodiments, each earpiece weighsbetween about 1 and about 10 grams (e.g., about 9 grams or less or about4 grams or less).

Earpieces of the present invention may possess any suitable heattransfer properties. In some embodiments, the earpiece(s) is/are moreefficiently heated than cooled. For example, the earpiece(s) may have aslew rate of about 15° C. per minute or greater during delivery of acooling stimulus and a slew rate of about 20° c. per minute or greaterduring delivery of a warming stimulus.

Earpieces of the present invention may comprise a thermally conductivecovering. For example, a thermally conductive cushion may cover one ormore portions of the earpiece(s) (e.g., the portion of an earpiece thatis inserted into the ear canal of a patient during use may be covered ina thermally conductive cushioning material to increase thermal contactbetween the earpiece and the ear canal (i.e., by conforming to the shapeof the ear canal)). The thermally conductive covering may comprise anysuitable material, including, but not limited to, coating materials thatmust be reapplied to the earpiece(s) before each use (e.g., water,water-based lubricants, thermal grease, gels and the like) and reusablecoating materials (e.g., a thermally conductive plastic sheath orsleeve).

Earpieces of the present invention may comprise a thermally insulatingcovering. For example, an insulating sleeve may cover one or moreportions of the earpiece(s) (e.g., the portion of an earpiece thatremains outside the ear canal of a patient during use may be covered inan insulating sleeve to reduce heat transfer between the earpiece andthe outer ear of the patient). The insulating covering may comprise anysuitable material, including, but not limited to, coating materials thatmust be reapplied to the earpiece(s) before each use (e.g., mineral oil,polypropylene, gels and the like) and reusable coating materials (e.g.,a thermally insulative sheath or sleeve). In some embodiments, thethermally insulating covering comprises a silicone sleeve.

Earpieces of the present invention may comprise an electricallyinsulating covering. For example, an electrically insulating coating maycover one or more portions of the earpiece(s) (e.g., the portion of anearpiece that is inserted into the ear canal of a patient during use maybe coated with an electrically insulating coating to prevent electricalconductance between the earpiece and the ear canal). The electricallyinsulating covering may comprises any suitable material, including, butnot limited to, metal oxides (e.g., aluminum oxide), glass, porcelainand composite polymer materials. In some embodiments, the surface of anearpiece comprising aluminum is anodized to produce an aluminum oxidecoating that electrically insulates the surface of the earpiece.

Earpieces of the present invention may comprise a protective coating.For example, a protective coating may cover one or more portions of theearpiece(s) (e.g., the portion of an earpiece that is inserted into theear canal of a patient during use may be coated with a protectivecoating to prevent the underlying surface of the earpiece from cominginto contact with the surface of the ear canal during use). Theprotective coating may comprise any suitable material, including, butnot limited to, metals and metal alloys (gold, silver, copper and alloysthereof).

As will be appreciated by one of skill in the art, earpieces of thepresent invention may comprise a single covering/coating that fulfillsmultiple purposes. For example, the a thermally conductive coatingapplied to the portion of an earpiece that is inserted into the earcanal of a patient during use may also prevent the underlying surface ofthe earpiece from coming into contact with the surface of the ear canalduring use.

As will be appreciated by one of skill in the art, earpieces of thepresent invention may comprise multiple coatings. For example, theearpiece(s) may comprise both a thermally conductive covering and athermally insulative covering (e.g., a thermally conductive cushion maycover the portion of an earpiece that is inserted into the ear canal ofa patient during use and an insulating sleeve may cover the portion ofan earpiece that remains outside the ear canal of a patient during use).

As shown in FIGS. 18A-18C, an earpiece 12 of the present invention maycomprise a base cavity 120, a tip cavity 121, one or more base apertures122, and a pressure-relief channel 123.

The base cavity 120 may be configured to receive a TED such that the TEDmay be thermally coupled to the earpiece 12 by mounting the TED on aninterior cavity surface of the base cavity 120.

The tip cavity 121 may be configured to receive a sensor (e.g., a sensorconfigured to detect the temperature of the earpiece).

The base apertures 122 may be configured to provide a passageway for oneor more wires and/or cables (e.g., a thermal stimulation lead connectedto a TED, a wire connected to the sensor 14, etc.).

The pressure-relief channel 123 may be configured to provide a pathwaythrough which air and/or moisture may flow during and/or after insertionof the earpiece 12 into the ear canal of a patient (e.g., to reduce thepressure in the ear canal during and/or after insertion of the earpiece12 and/or to allow moisture to escape the ear canal during and/or afterinsertion of the earpiece 12). The pressure-relief channel 123 may be ofany suitable length and depth (i.e., any length/depth that is sufficientto provide air flow from the interior of the ear canal at the distal tipof the earpiece to the external air outside of the ear canal duringand/or after insertion of the earpiece 12). For example, thepressure-relief channel 123 may be generally as long as a side of theearpiece 12 and may be about 0.5 millimeters to 2 millimeters deep. Thepressure-relief channel 123 may be located in any suitable locationin/on the earpiece (e.g., embedded in an outer surface of earpiece 12 orpassing through the interior of the earpiece 12 so as to provide aconduit between the interior of the ear canal and the exteriorenvironment).

C. Thermoelectric Device

The vestibular stimulation device may comprise one or more TEDs. TEDs ofthe present invention may be operatively connected to one or morecontrollers and may be used deliver one or more thermal waveforms to thevestibular system and/or the nervous system of a patient (e.g., bywarming and/or cooling an earpiece inserted into the ear canal of saidpatient).

Any suitable thermoelectric device can be used to carry out the presentinvention, including, but not limited to, those described U.S. Pat. Nos.5,974,806, 6,229,123, 6,977,360, 7,024,865, 7,098,393, 7,202,443 and7,205,675; in U.S. Patent Publication Nos. 2004/0199266 and 2010/0198204and 2010/0198282; in U.S. patent application Ser. No. 12/970,312 andSer. No. 12/970,347); and in U.S. Provisional Application Nos.61/497,761, the disclosure of each of which is incorporated herein byreference in its entirety. For example, the vestibular stimulationdevice comprises one or more thin film TEDs (including, but not limitedto, those described in U.S. Pat. No. 6,300,150 and U.S. PatentPublication Nos. 2006/0086118 and 2007/0028956).

TEDs of the present invention may comprise any suitable material. Forexample, the TED(s) may comprise a thermoelectric material such asbismuth telluride. In some embodiments, the TED(s) comprise a P-typethermoelectric element and an N-type thermoelectric element that areelectrically coupled in series and thermally coupled in parallel.

TEDs of the present invention may be of any suitable size/shape. In someembodiments, the TED(s) is/are of a generally rectangular shape, withtypical rectangular areas being about 2×1 mm or about 5×2 mm or more andwith a typical height profile of about 1.0 mm, about 0.65 mm or about0.5 mm or less.

TEDs of the present invention may be configured to sense the temperatureof the earpiece(s) and/or the heat sink(s) with which it is associated.

As will be appreciated by one of skill in the art, in those embodimentscomprising a plurality of TEDs, the TEDs may be arranged in any suitablemanner. For example, the TEDs may be positioned adjacent one another ina linear array, a two-dimensional array or a three-dimensional array(e.g., at a density of about 5, 10 or 20 per square centimeter to about100, 200 or 400 per square centimeter or more).

As will be appreciated by one of skill in the art, in those embodimentscomprising a plurality of TEDs, the TEDs may be thermally coupled to oneanother. For example, the TEDs may be thermally coupled to one another(e.g., through a common heat sink) such that thermal energy displaced byone TED can be at least partially offset by thermal energy displaced byanother TED (e.g., by heating tissue with one TED while cooling adjacenttissue with an adjacent TED).

D. Heat Sink

The vestibular stimulation device may comprise one or more heat sinks.In some embodiments, at least one heat sink is thermally coupled to eachearpiece. In some embodiments, each TED thermally coupled to an earpieceis thermally coupled between the earpiece and at least one heat sink. Insome embodiments, the heat sink(s) may be thermally isolated from theearpiece(s) except insofar as they are thermally coupled to oppositesides of the TED(s). In those embodiments comprising a pair ofearpieces, each earpiece may be thermally coupled to a separate heatsink and/or to a common heat sink.

Any suitable heat sink can be used to carry out the present invention,including, but not limited to, those described in U.S. PatentPublication Nos. 2010/0198204 and 2010/0198282); in U.S. patentapplication Ser. No. 12/970,312 and Ser. No. 12/970,347; and in U.S.Provisional Application Nos. 61/497,761, the disclosure of each of whichis incorporated herein by reference in its entirety.

Heat sinks of the present invention may comprise any suitable material,including, but not limited to, metal alloys. For example, the heatsink(s) may comprise aluminum or an aluminum alloy (e.g., 6061aluminum).

Heat sinks of the present invention may be of any suitable size/shape.In some embodiments, the heat sink(s) comprise(s) a plurality of fins.Such fins may be from about 1 to about 500 mm in height, preferablyabout 1 to about 100 mm. In some embodiments, each heat sink weighsbetween about 30 grams and about 70 grams.

Heat sinks of the present invention may be passively and/or activelycooled. For example, each heat sink may be associated with one of morefans configured to increase air flow over the heat sink, therebyfacilitating heat dissipation from the heat sink.

E. Sensors

The vestibular stimulation device may comprise one or more sensors. Insome embodiments, the sensor(s) is/are configured to transmit controllerfeedback data, data associated with the delivery of one or more thermalwaveforms to the vestibular system and/or the nervous system of apatient and/or data associated with the fit of one or more earpieces tothe controller. In some such embodiments, the controller is configured(e.g., with computer instructions (i.e., software)) to adjust one ormore attributes of TED activation (e.g., magnitude, duration, wavepattern, etc.) in response to feedback data received from the sensor(s)with which it is associated. The sensor(s) may be configured to transmitdata to the controller over any suitable wired or wirelesscommunications channel, including, but not limited to, a LAN, theInternet, a public telephone switching network, Bluetooth, WLAN and thelike.

Any suitable sensor can be used to carry out the present invention,including, but not limited to, those described in U.S. Pat. Nos.7,578,793, 7,558,622, 7,396,330, 7,215,994, 7,197,357, 7,087,075 and6,467,905; in U.S. Patent Publication No. 2010/0198282; in U.S. patentapplication Ser. No. 12/970,312 and Ser. No. 12/970,347; and in U.S.Provisional Application Nos. 61/497,761, the disclosure of each of whichis incorporated herein by reference in its entirety. For example, thevestibular stimulation device may comprise one or more of a galvanicskin resistance sensor, a position sensor, a motion detector, a bloodpressure sensor, a heart rate sensor, a blood gas level sensor, anelectrocardiogram sensor, an electroencephalogram sensor, anelectrooculogram sensor, an electronystragmography sensor, a breathingrate sensor, a nystagmus sensor and a temperature sensor. Numerous suchsensors are known and can be operatively associated with the systemsdescribed herein in accordance with known techniques or variationsthereof that will be apparent to those skilled in the art given thepresent disclosure.

In some embodiments, the vestibular stimulation device comprises one ormore temperature sensors. In some such embodiments, the vestibularstimulation device comprises a temperature sensor configured to providecontroller feedback data associated with the temperature of the heatsink, a temperature sensor configured to provide controller feedbackdata associated with the temperature of the earpiece, a temperaturesensor configured to provide controller feedback data associated withthe temperature of the ear canal of the patient and/or a temperaturesensor configured to provide controller feedback data associated withthe temperature of the inner ear of the patient. In some embodiments,each earpiece comprises a sensor (e.g., an infrared sensor) configuredto detect the temperature of the inner ear.

F. Headband

The vestibular stimulation device may comprise a headband. In someembodiments, the headband is configured to position the earpiece(s) inthe ear canal(s) of a patient. In some embodiments the headband isadjustable. It should be appreciated that, while the headband may beworn over the head, it may also be positioned under the chin, behind thehead and/or over the ear(s).

Any suitable headband can be used to carry out the present invention,including, but not limited to, those described in U.S. patentapplication Ser. Nos. 12/704,872; 12/970,312 and Ser. No. 12/970,347; inU.S. Provisional Application Nos. 61/287,873; 61/303,984, 61/304,059 and61/497,761, the disclosure of each of which is incorporated herein byreference in its entirety.

G. Operation.

As noted above with respect to FIG. 1, the vestibular stimulation device1 may comprise a controller 11 that is operatively connected to a TED 13a that is thermally connected to an earpiece 12 a that is configured soas to be insertable into the left ear canal of a patient and to a TED 13b that is thermally connected to an earpiece 12 b that is configured soas to be insertable into the right ear canal of a patient. In some suchembodiments, the controller 11 (e.g., a controller 11 as described abovewith respect to FIG. 14) is configured to enable a user to deliver oneor more thermal waveforms to the vestibular system and/or the nervoussystem of a patient by:

-   -   a) generating and/or modifying the parameters, indications        and/or approvals of one or more thermal waveforms using the        waveform module 11 a;    -   b) transmitting the generated/modified parameters, indications        and/or approvals to the treatment module 11 b and/or storing the        generated/modified parameters, indications and/or approvals in        the waveform database 11 h;    -   c) generating a prescription comprising a set of instructions        for delivering one or more thermal waveforms to the vestibular        system and/or the nervous system of the patient by:        -   i) receiving one or more thermal waveforms from the waveform            module 11 a and providing instructions as to how each            thermal waveform is to be administered to the patient using            the treatment module 11 b; or        -   ii) selecting one or more thermal waveforms from the            waveform database 11 h and providing instructions as to how            each thermal waveform is to be administered to the patient            using the treatment module 11 b;    -   d) transmitting the generated prescription to the control module        11 c and/or storing the generated prescription in the        prescription database 11 i; and/or    -   e) delivering one or more thermal waveform(s) to the vestibular        system and/or the nervous system of the patient by:        -   i) receiving a prescription comprising a set of instructions            for delivering one or more thermal waveforms to the            vestibular system and/or the nervous system of the patient            from the treatment module 11 b and activating the TEDs 13 a,            13 b in accordance with the instructions; or        -   ii) retrieving a prescription comprising a set of            instructions for delivering one or more thermal waveforms to            the vestibular system and/or the nervous system of the            patient from the prescription database 11 i and activating            the TEDs 13 a, 13 b in accordance with the instructions.            In some such embodiments, the controller 11 (e.g., a            controller 11 as described above with respect to FIG. 15) is            configured to enable a user to deliver one or more thermal            waveforms to the vestibular system and/or the nervous system            of a patient by:    -   a) receiving and/or retrieving the parameters, indications        and/or approvals of one or more thermal waveforms from a        registry and/or a portable memory device using the network        module 11 d;    -   b) storing the received/retrieved parameters, indications and/or        approvals in the waveform database 11 h and/or transmitting the        received/retrieved parameters, indications and/or approvals to        the waveform module 11 a and/or the treatment module 11 b;    -   c) generating and/or modifying the parameters, indications        and/or approvals of one or more thermal waveforms using the        waveform module 11 a;    -   d) transmitting the generated/modified parameters, indications        and/or approvals to the treatment module 11 b and/or storing the        generated/modified parameters, indications and/or approvals in        the waveform database 11 h;    -   e) receiving and/or retrieving a prescription from a registry        and/or a portable memory device using the network module 11 d;    -   f) storing the received/retrieved prescription in the        prescription database 11 i and/or transmitting the        received/retrieved prescription to the treatment module 11 b        and/or the control module 11 c;    -   g) generating a prescription comprising a set of instructions        for delivering one or more thermal waveforms to the vestibular        system and/or the nervous system of the patient by:        -   i) receiving one or more thermal waveforms from the network            module 11 d and/or the waveform module 11 a and providing            instructions as to how each thermal waveform is to be            administered to the patient using the treatment module 11 b;        -   ii) selecting one or more thermal waveforms from the            waveform database 11 h and providing instructions as to how            each thermal waveform is to be administered to the patient            using the treatment module 11 b;        -   iii) receiving a prescription from the network module 11 d            and modifying the instructions as to how each thermal            waveform is to be administered to the patient using the            treatment module 11 b;        -   ii) retrieving a prescription from the prescription database            11 i and modifying the instructions as to how each thermal            waveform is to be administered to the patient using the            treatment module 11 b;    -   h) transmitting the generated prescription to the control module        11 c and/or storing the generated prescription in the        prescription database 11 i; and/or    -   i) delivering one or more thermal waveform(s) to the vestibular        system and/or the nervous system of the patient by:        -   i) receiving a prescription comprising a set of instructions            for delivering one or more thermal waveforms to the            vestibular system and/or the nervous system of the patient            from the treatment module 11 b and activating the TEDs 13 a,            13 b in accordance with the instructions; or        -   ii) retrieving a prescription comprising a set of            instructions for delivering one or more thermal waveforms to            the vestibular system and/or the nervous system of the            patient from the prescription database 11 i and activating            the TEDs 13 a, 13 b in accordance with the instructions.

Also as noted above with respect to FIG. 1, the vestibular stimulationdevice 1 may further comprise a pair of sensors 14 a, 14 b, wherein oneof the sensors 14 a is operatively connected to the earpiece 12 a thatis configured so as to be insertable into the left ear canal of thepatient, wherein the other sensor 14 b is operatively connected to theearpiece 12 b that is configured so as to be insertable into the rightear canal of the patient and wherein the controller 11 is operativelyconnected to each of the sensors 14 a, 14 b via a wireless connection 17a, 17 b. In some such embodiments, controller 11 (e.g., a controller 11as described above with respect to FIG. 15) is configured such thatcontroller feedback data received from the sensors (e.g., dataassociated with the temperature of the earpiece(s), data associated withthe temperature of the patient's ear canal(s), data associated with therate at which an earpiece is warmed/cooled in response to awarming/cooling stimulus, etc.) is used by the control module 11 c toensure that the appropriate thermal waveform(s) is delivered to thevestibular system and/or the nervous system of the patient (e.g., thecontrol module 11 c may be configured to increase/decrease the magnitudeof TED 13 a activation if/when controller feedback data from the sensor14 b associated with the left earpiece 12 a indicates that thetemperature of the earpiece 12 a is not at the appropriate temperaturegiven the parameters of the prescribed thermal waveform).

As shown in FIG. 19, in some embodiments, the vestibular stimulationdevice comprises a controller 11 and a headset 18. As shown therein, theheadset may comprise a headband 18 h configured to position a firstearpiece 12 a in the left ear canal of a patient and to position asecond earpiece 12 b in the right ear canal of the subject; a first heatsink thermally coupled to the first earpiece 12 a (as shown, the firstheat sink is concealed within a first housing 18 a, the ventilationapertures 18 av of which allow for heat exchange between the first heatsink and the ambient environment), a second heat sink thermally coupledto the second earpiece 12 b (as shown, the first heat sink is concealedwithin a second housing 18 b, the ventilation apertures 18 bv of whichallow for heat exchange between the second heat sink and the ambientenvironment); a first TED thermally coupled between the first earpiece12 a and the first heat sink (as shown, the first TED is concealedwithin the first housing 18 a); a second TED 13 b thermally coupledbetween the second earpiece 12 b and the second heat sink (as shown, thesecond TED 13 b is concealed within the second housing 18 b); a firstsensor operatively connected to the first TED and the controller 11 (asshown, the first sensor is concealed within the first earpiece 12 a; asecond sensor operatively connected to the second TED and the controller11 (as shown, the second sensor is concealed within the second earpiece12 a; a first cushion 18 c connected to the first housing 18 a and asecond cushion 18 d connected to the second housing 18 b. In some suchembodiments, the controller is operatively connected to the first andsecond TEDs by a pair of thermal stimulation leads 16 a, 16 b. In somesuch embodiments, the controller 11 is operatively connected to thefirst and second sensors via a wireless connection (e.g., via aradiofrequency transceiver or a Bluetooth connection). In some suchembodiments, one or both of the first and second cushions 18 c, 18 d isconfigured to be adjustable (e.g., the first cushion 18 c and/or thesecond cushion 18 d may comprise an inner chamber that may beinflated/deflated to adjust the firmness and/or the size of the cushion,thereby allowing a user to adjust the fit of the vestibular stimulationdevice (i.e., to adjust how far the first and/or second earpiece 12 a,12 b inserts into the patient's ear canal by increasing/decreasing theamount of gas/liquid in the inner chamber)).

As discussed above with respect to FIG. 19, in some embodiments of thepresent invention, various components of the vestibular stimulationdevice 1 are concealed within the first and/or second housings 18 a, 18b. FIG. 20 provides an exploded view of a first housing 18 a accordingto some embodiments of the present invention. As shown therein, thefirst housing 18 a may conceal a first TED 13 a; a first sensor 14 a; afirst heat sink 15 a, said first heat sink 15 a comprising a first heatsink base 15 ab, a first heat sink spacer 18 as, a plurality of fins 15af and a plurality of cable apertures 15 ac to provide passageways forone or more wires and/or cables (e.g., one or wires connected to thefirst TED 13 a and/or one or wires connected to the first sensor 14 a),and two heat dissipating fans 19 a, 19 b. The first earpiece 12 a may bethermally connected to the first TED 13 a and the first heat sink 15 aas shown in FIGS. 21A-21B. The first TED 13 a may be positioned on thetop surface 15 as′ of the heat sink spacer 15 as and inside the basecavity 120 a of the first earpiece 12 a and may be adhered to the heatsink 15 a and/or the first earpiece 12 a using a thermally conductiveadhesive (e.g., silver paste). The first sensor 14 a may be positionedinside the tip cavity 121 of the first earpiece 12 a and may beconfigured to provide controller feedback data associated with thetemperature of the first earpiece 12 a to the controller (as discussedabove). Upon activation, the heat dissipating fans 19 a, 19 b mayfacilitate the transfer of heat between the first heat sink 15 a and theambient environment by increasing air flow across the first heat sink 15a. The outer member 18 ao of the first housing 18 a comprisesventilation apertures 18 av to further facilitate the transfer of heatbetween the first heat sink 15 a and the ambient environment (byincreasing the flow of air across the first heat sink 15 a) and a cableaperture 18 ac to provide a passageway for one or more wires and/orcables (e.g., the thermal stimulation lead 16 a and/or one or wiresconnected to the first sensor 14 a). The inner member 18 ai of the firsthousing 18 a comprises an earpiece aperture 18 ae through which thedistal portion of the first earpiece 12 a protrudes. As will beappreciated by one skilled in the art, the second housing 18 b may besimilarly configured.

3. Waveform Stimulus and Treatment Sessions

“Waveform” or “waveform stimulus” as used herein refers to the thermalstimulus (heating, cooling) delivered to the ear canal of a subjectthrough a suitable apparatus to carry out the methods described herein.“Waveform” is not to be confused with “frequency,” the latter termconcerning the rate of delivery of a particular waveform. The term“waveform” is used herein to refer to one complete cycle thereof, unlessadditional cycles (of the same, or different, waveform) are indicated.As discussed further below, time-varying waveforms are preferred overconstant temperature applications in carrying out the present invention.

In some embodiments, the waveform stimulus is an actively controlledwaveform or actively controlled time-varying waveform. “Activelycontrolled waveform” or “actively controlled time-varying waveform” asused herein refers to a waveform stimulus in which the intensity of thestimulus or temperature of the earpiece delivering that stimulus, isrepeatedly adjusted, or substantially continuously adjusted or driven,throughout the treatment session, typically by control circuitry or acontroller in response to active feedback from a suitably situatedtemperature sensor (e.g., a temperature sensor mounted on the earpiecebeing driven by a thermoelectric device), so that drift of the thermalstimulus from that which is intended for delivery which would otherwiseoccur due to patient contact is minimized.

In general, a waveform stimulus used to carry out the present inventioncomprises a leading edge, a peak, and a trailing edge (see, e.g., FIG.22). If a first waveform stimulus is followed by a second waveformstimulus, then the minimal stimulus point therebetween is referred to asa trough.

The first waveform of a treatment session is initiated at a start point,which start point may be at or about the subject's body temperature atthe time the treatment session is initiated (typically a range of about34 to 38 degrees Centigrade, around a normal body temperature of about37 degrees Centigrade (temperature changes and amplitudes are given withreference to normal body temperature herein, unless indicatedotherwise). The lower point, 34, is due to the coolness of the earcanal. It typically will not be above about 37 unless the patient isfebrile). Note that, while the subject's ear canal may be slightly lessthan body temperature (e.g., about 34 to 36 degrees Centigrade), thestarting temperature for the waveform is typically body temperature (thetemp of the inner ear), or about 37 degrees Centigrade. In someembodiments, however, the temperature of the treatment device may nothave equilibrated with the ear canal prior to the start of the treatmentsession, and in such case the start point for at least the firstwaveform stimulus may be at a value closer to room temperature (about 23to 26 degrees Centigrade).

The waveform leading edge is preferably ramped or time-varying: that is,the amplitude of the waveform increases through a plurality of differenttemperature points over time (e.g., at least 5, 10, or 15 or moredistinct temperature points, and in some embodiments at least 50, 100,or 150 or more distinct temperature points, from start to peak). Theshape of the leading edge may be a linear ramp, a curved ramp (e.g.,convex or concave; logarithmic or exponential), or a combinationthereof. A vertical cut may be included in the waveform leading edge, solong as the remaining portion of the leading edge progresses through aplurality of different temperature points over time as noted above.

The peak of the waveform represents the amplitude of the waveform ascompared to the subject's body temperature. In general, an amplitude ofat least 5 or 7 degrees Centigrade is preferred for both heating andcooling waveform stimulation. In general, an amplitude of up to 20 or 22degrees Centigrade (below body temperature) is preferred for coolingwaveform stimulation. In general, an amplitude of up to 8, 10 or 12degrees Centigrade (above body temperature) is preferred for heatingwaveform stimulus. The peak of the waveform may be truncated (that is,the waveform may reach an extended temperature plateau), so long as thedesired characteristics of the leading edge, and preferably trailingedge, are retained. For heating waveforms, truncated peaks of longduration (that is, maximum heat for a long duration) are less preferred,particularly at higher heats, due to potential burning sensation.

The waveform trailing edge is preferably ramped or time-varying: thatis, the amplitude of the waveform decreases through a plurality ofdifferent temperature points over time (e.g., at least 5, 10, or 15 ormore distinct temperature points, or in some embodiments at least 50,100, or 150 or more distinct temperature points, from peak to trough).The shape of the trailing edge may be a linear ramp, a curved ramp(e.g., convex or concave; logarithmic or exponential), or a combinationthereof. A vertical cut may again be included in the waveform trailingedge, so long as the remaining portion of the trailing edge progressesthrough a plurality of different temperature points over time as notedabove.

The duration of the waveform stimulus (or the frequency of that waveformstimulus) is the time from the onset of the leading edge to either theconclusion of the trailing edge or (in the case of a vertically cutwaveform followed by a subsequent waveform). In general, each waveformstimulus has a duration, or frequency, of from one or two minutes up toten or twenty minutes.

A treatment session may have a total duration of one, two, five or tenminutes, up to 20 or 40 minutes, or even 60 or 80 minutes, or more,depending on factors such as the specific waveform or waveformsdelivered, the patient, the condition being treated, etc. In a treatmentsession, a plurality of waveforms may be delivered in sequence (see,e.g. FIG. 22). In general, a treatment session will comprise 1, 2 or 3waveforms, up to about 10 or 20 waveforms delivered sequentially. Eachindividual waveform may be the same, or different, from the other (see,e.g., FIG. 22). When a waveform is followed by a subsequent waveform,the minimum stimulus point (minimum heating or cooling) between twoconsecutive peaks is referred to as the trough. Like a peak, the troughmay be truncated, so long as the desired characteristics of the trailingedge, and the following next leading edge, are retained. While thetrough may represent a return to the subject's current body temperature,in some embodiments minor thermal stimulation (cooling or heating; e.g.,by 1 or 2 degrees up to 4 or 5 degrees Centigrade) may continue to beapplied at the trough (or through a truncated trough). The treatmentsessions may be continuous, or may be interrupted by short pauses of upto 1 or 2 minutes, or more.

Treatment sessions are, in some embodiments, once a day, though in someembodiments more frequent treatment sessions (e.g. two or three times aday) may be employed. Day-to-day treatments may be by any suitableschedule: every day; every other day; twice a week, etc., as needed bythe subject. The overall pattern of treatment is thus typically chronic(in contrast to “acute,” as used in one-time experimental studies).

In some embodiments, the time-varying thermal waveforms are sufficientto induce nystagmus over a time of at least four, five, ten, or fifteenminutes, or more, up to a time of thirty minutes or one hour, or more.Nystagmus may be as measured by videonystagmography and/or byelectronystagmography, and may increase or decrease or even cease forbrief periods over the treatment period, but is substantially presentfor the treatment period.

4. Thermal Model of Caloric Vestibular Stimulation

The thermodynamic details of how the cupola is actually stimulated, theultimate cause of excitation or inhibition of a given branch of thevestibulocochlear nerve, is important in describing the principles ofthe present invention.

The temporal bone, which overlies the inner ear, is filled with voids(filled with cells and fluids but sometimes just air) leading to a netthermal conductivity that may be lower than that of dense bone.Zeigmeister & Bock (Acta Otolaryngologica 88, 105-9 (1979)) indicatethat the effective thermal diffusivity will vary in patients based onthe degree of pneumatization of the temporal bone. However, this isgenerally based on observations of the induction of nystagmus, which isa secondary effect of the first-order stimulation by direct afferents ofthe vestibular nerve.

Compact bone in the region of interest provides the most efficientthermal pathway. X-rays of the region indicate that there are highconductivity thermal paths (in 3-dimensions) that compete with pathsthrough the bone with air pockets. In the model below, a value ofthermal diffusivity closer to that of compact bone is chosen. Toinitiate caloric vestibular stimulation, the most important “target” isthe most distal extent of the external auditory meatus (ear canal). Airis an effective thermal insulator and therefore the air gap in themiddle ear (variously referred to as the mastoid antrum or cavity,epitympanic cavity) is not the primary pathway for thermal conductionfrom the ear canal to the horizontal (also called lateral) semicircularcanal (however, there is some evidence of radiative cooling of thedistal wall of the mastoid cavity during the initial induction of CVS).That is, the temporal bone is the primary thermal conduit and thus theCVS thermal source should be in intimate contact with it to ensure goodthermal transfer.

The obvious boundary for the CVS probe is the tympanic membrane, whichmust not be pierced. For water and air calories, the entire ear canal isfilled and this is advantageous in terms of contact with the temporalbone (though one does have to guard against the development of stagnanteddies against the ear drum). Once the CVS source starts to act on thetemporal bone, the thermal wave travels around the epitympanic cavity(most strongly along inner surface, which is compact bone, at first)until it reaches the far side of the cavity, above the point where thestapes contacts the oval window. The horizontal (also called lateral)semicircular canal can be viewed as a ring embedded in bone that has apoint of close tangency to the epitympanic cavity. It is this section ofthat canal that experiences the effect of the thermal wave first. As thethermal wave progresses, it moves deeper into the distal side of theepitympanic cavity and ultimately reaches the distal side of thehorizontal canal.

The object of CVS is to develop (and maintain) a temperature differenceacross the diameter of the horizontal canal. The speed with which thetemperature gradient is experienced by the horizontal canal depends onthe cooling effects of blood entering and leaving the region and anyindividual variation in the anatomy of a patient. The fit of theearpiece is an important as well. It should be noted that the endolymphin the other two semicircular canals and in the utricle and saccule mayalso develop convection currents that lead to altered phasic firing, butfor simplicity we focus on the horizontal canal.

A large caloric stimulus leads to a shorter duration of stimulation. Arobust thermal wave will, more quickly, flow deeper into the boneyhousing of the horizontal canal and the temperature gradient across itwill be nullified more quickly. The various thermal models in theliterature (e.g., Proctor et al., Acta Otolaryngol 79, 425-435 (1975))simplify the real anatomy even further and consider a layer of skin ontop of a honey region that contains the semicircular canal.

Moving to the semicircular canals themselves, there are anatomicfeatures of interest for modeling CVS. The inner wall of each canal is atough, membranous structure, which contains the endolymph (TheVestibular System; Highstein et al. editors, Springer (New York), 2004).The membranous tube is connected to a layer of lamellar bone, whichforms the hard (enduring) portion of the canal. Between the honey layerand membranous layer is another fluid called the perilymph. Thereforethe literature refers to a boney and a membranous labyrinth whendescribing the semicircular canals. The membranous tube is thought notto deform appreciably and therefore is viewed as being rigidly attachedto the temporal bone and moves with the head. The endolymph, however,moves “independently” in the canal. Note that the cupula, a gelatinousdiaphragm in the ampulla (the widened portion of the semicircularcanal), is a complete barrier in the canal and thus endolymph cannottruly circulate around the loop of the canal. Hence the cupula is pushedto one side or the other by movement of the endolymph. Intuitively, thismovement is most easily understood by thinking about sudden rotationabout the vertical axis of the body. The endolymph will “slosh upagainst” the cupula, pushing it in the direction of motion of theendolymph. As we will see, the effects of the present invention on theendolymph is less intuitive and involves complexities.

A key feature of the movement of the cupula is that in one direction itleads to an increase in the firing rate of the hair cells in the crista(innervated end of the ampulla) whereas movement in the oppositedirection leads to a decrease in the rate (relative to a tonic orsteady-state level of roughly 100 Hz). Thus there is an inhibitory orexcitatory influence on the tonic firing rate of the afferent vestibularnerve innervating the horizontal canal based on the direction ofendolymph movement. This influence is, indeed, what leads to the onsetof nystagmus during CVS with a directional dependence on the temperatureof the stimulus, though nystagmus is de-coupled (in time) from theinitial activation of the brainstem.

One of the complex aspects of the collection of semicircular canals isthat they have fluid connections between them. Therefore, they canexchange endolymph. This means that CVS to the horizontal canal canactually have effects on the other two canals (anterior and posterior).A further complication of the naming of the anatomy is that thehorizontal canal is not really horizontal, but tilts by approximately 20degrees so that it is high on the anterior side of the head. Thus, whena patient tilts back 70 degrees (the head lying on a 20 degree inclineabove a horizontal surface), the “horizontal” canal is then oriented sothat the loop is roughly vertical. For diagnostic CVS, the patient isoften reclined in this manner because it is thought that the effect ofCVS is maximized as a result of receiving the stimulation while in thisposture.

The thermodynamics of endolymph flow in the semicircular canals has beenthe subject of several papers. In classical fluid mechanics, amathematical formalism for non-compressible fluids called theNavier-Stokes equations must be used to understand flow dynamics Inpractice, this is a complicated undertaking and it is often necessary toresort to numerical modeling. Here, we present an idealized model of thehorizontal SCC and how thermodynamics influences the character of neurostimulation.

FIG. 23 shows an idealized form of the horizontal SCC (stippled) that isbeing heated on one side (wavy lines) and cooled on the other(cross-hatched). The cupula is shown in dark grey and the arrowrepresent endolymph flow. On the right, an expanded region representingthe ampulla has been added. When the endolymph is heated, it will rise(less dense, or expanded in volume) and push on the center of thecupula. There is a small boundary layer of endolymph that adheres morestrongly to the sidewall of the canal and we ignore that here. Once theendolymph hits the cupula, it will exert most of the distortioncentrally because the cupula is most easily deformed there and becausethere is a circulatory aspect to the convection driven endolymph: riseup the center and fall down along the sides. The bulge of the ampullaintroduces a sudden expansion in volume, which will complicate themovement of convection driven endolymph (shown conceptually on theright). The same basic convective flow will occur, but the ampulla willmost likely create more turbulence and therefore, potentially, morecomplicated low amplitude movement of the cupula. In analyzingnystagmus, a simple view that considers only the upward displacement ofthe cupula is adopted (and that's reasonable for the gross nystagmicmovement). Most likely the cupula exhibits time-varying “flutter,”especially for lower amplitude distortion. Under rotational stimulus,the cupula is pressed to one side and then rebounds. Caloricstimulation, especially when the temperature gradient is weak orchanging, sets up a much more complicated series of deformationalforces. Therefore one would expect a complex time series of excitatoryand inhibitory firings of the hair cells (at the “base” of the cupulacalled the crista). It is again important to note the great sensitivityto motion of the cupula and its ability to respond across a wide dynamicrange of impulsive forces (big bumps versus subtle head movements).Further, as noted earlier, the three SCC's do communicate by fluidconnections (restricted ones), and it is reasonable to expect that somelevel of attenuated stimulation of the anterior and posterior SCC's willoccur both directly (they respond to caloric stimulation) and inconjunction with stimulation of the horizontal canal. And as noted,endolymph motion in the utricle and saccule, set up by convectioncurrents, may also lead to changes in the phasic firing rates of somevestibular nerve afferents.

Let us briefly consider the case of stimulation of the horizontal SCC ina less favorable position for CVS-generated nystagmus—that is, when thehead is tilted somewhat forward (the horizontal canal is close to beinghorizontal). The literature seems to maintain that inducing nystagmus ata 20° forward tilt will not occur. However, even in that case one wouldexpect some time-varying deformation of the cupula due to turbulence inthe endolymph.

When the horizontal canal is close to the horizontal position in thegravitational field (referring again to the analogy of a bubble influid), the heated endolymph will still tend to move up to the cupulaand deform it. There is some evidence in the literature that the haircells fire with a chaotic time pattern, suggesting again that turbulencemay cause some “flutter” of the cupula due to convection currents in theendolymph.

Heating Versus Cooling Caloric Vestibular Stimulation.

Endolymph, the active fluid in the vestibular labyrinth, ispredominantly water. Water expands and contracts in a nonlinear fashionwith temperature. A larger change in volume occurs at temperature deltasabove body temperature (37° C.) than below it. For example, to achievethe same change in volume in going from 37° C. to 47° C., one needs togo from 37° C. to 23° C. Since volume change corresponds to thedisplacement of the cupula in the horizontal semicircular canal, itcorresponds to the magnitude of the phasic frequency shift away from thetonic firing frequency of the hair cells, which innervate the vestibularnerve.

Additionally, a cold caloric stimulus acts to reduce the firingfrequency whereas a warm caloric stimulus increases it. Taking the tonicfiring rate to be roughly 100 Hz, cold CVS can only, maximally, reducethe firing rate to close to 0 Hz. Warm CVS, on the other hand, canincrease the phasic firing frequency beyond 200 Hz, perhaps to as highas 400 Hz. This creates an additional asymmetry that favors warm CVS interms of the intensity of stimulus to the cochlear nerve.

Zhou et al. (J Neurochem 95, 221-229 (2005)) posit that stimulation ofthe fastigial nucleus has a neuroprotective effect by frustratingapoptosis in mitochondria. CVS stimulates the fastigial nucleus. Thegoal is to prescribe properly titrated treatment by the presentinvention for patients across a range of diseases. The fMRI study byMarcelli et al. (“Spatio-temporal pattern of vestibular informationprocessing after brief caloric stimulation,” Eur J Radiol 70, 312-316(2009)) showed activation in the brainstem, cerebellum, thalamus, andinsular cortex after a brief (1.5 second) cold caloric stimulation. Theactivation lasted for more than 200 seconds and was most noticeable inthe brainstem. Further, this study did not see a correlation betweenactivation and the onset time for nystagmus (though they did not rulethis out completely).

There are three primary modes of carrying out the present invention: (1)time varying excitatory; (2) time varying inhibitory; and (3) timevarying excitatory and inhibitory. The magnitude of the stimulus (i.e.,the temperature difference with respect to body temperature) is notindependent of the time over which the influence of that temperaturedelta will continue once the external thermal stimulus ceases. Forexample, the application of a 4° C. stimulus for 1 minute will result ina large magnitude effect on the endolymph that will frustrate a rapidchange back to a higher temperature. As noted above, such a pulse wouldlead to faster adaptation and would then become more variable as theendolymph warms and develops turbulent eddies. A lower magnitudestimulus can be varied more quickly, since the system is not driven sofar out of equilibrium.

Large amplitude, square waveform caloric vestibular stimulation resultsin a decreased ability to rapidly vary the “sign”(inhibitory/excitatory) of hair cell stimulation and leads to fasteradaptation effects (return towards tonic hair cell firings) andtherefore negates the advantage of longer CVS delivery duration. Thepresent invention provides a way to produce a full range of cupularstimulation patterns so as to effectively titrate chronic treatmentprotocols for patient benefit without losing efficacy due to adaptationand without inducing undesirable side effects that can accompany the useof current irrigator-type CVS devices.

5. Subjects for Treatment

Subjects may be treated with the present invention for various reasons.In some embodiments, disorders for which treatment may be carried outinclude, include, but are not limited to, headaches, depression, anxiety(e.g. as experienced in post-traumatic stress disorder (“PTSD”) or otheranxiety disorders), spatial neglect, Parkinson's disease, seizures(e.g., epileptic seizures), diabetes (e.g., type II diabetes), etc.Subjects may be treated to enhance cognition or cognitive reserve, toenhance long term memory, to enhance short term memory, to enhance longterm memory, etc.

Additional disorders and conditions that can be treated by the methodsand systems of the present invention include, but are not limited to,neuropathic pain (e.g., migraine headaches), brain injury (acute braininjury, excitotoxic brain injury, traumatic brain injury, etc.), spinalcord injury, body image or integrity disorders (e.g., spatial neglect),tinnitus, visual intrusive imagery, neuropsychiatric disorders (e.g.depression), bipolar disorder, neurodegenerative disorders (e.g.Parkinson's disease), asthma, dementia, insomnia, stroke, cellularischemia, metabolic disorders, (e.g., diabetes), post-traumatic stressdisorder (“PTSD”), addictive disorders, sensory disorders, motordisorders, and cognitive disorders.

“Headache” as used herein includes, but is not limited to, primaryheadaches such as migraine headaches, tension-type headaches, trigeminalautonomic cephalagias, and other primary headaches; as well as secondaryheadaches. See, e.g., International Headache Society ClassificationICHD-II.

“Migraine headaches” that may be treated by the invention may be acuteor chronic, and unilateral or bilateral. The migraine headache may be ofany type, including but not limited to migraine with aura, migrainewithout aura, hemiplegic migraine, ophthalmoplegic migraine, retinalmigraine, basilar artery migraine, abdominal migraine, vestibularmigraine, probable migraine, etc.

“Vestibular migraine” as used herein refers to migraine with associatedvestibular symptoms, including but not limited to head motionintolerance, unsteadiness, dizziness, and vertigo. “Vestibular migraine”as used herein includes, but is not limited to, those conditionssometimes also referred to as vertigo with migraine, migraine associateddizziness, migraine-related vestibulopathy, migrainous vertigo, andmigraine-related vertigo. See, e.g., R. Teggi et al., Headache 49,435-444 (2009).

“Tension-type headache” that may be treated by the invention includeinfrequent episodic tension-type headache, frequent episodictension-type headache, chronic tension-type headache, and probabletension-type headache, etc.

“Trigeminal autonomic cephalagias” that may be treated by the inventioninclude cluster headache, paroxysmal hemicranias, short-lastingunilateral neuralgiform headache attacks with conjunctival injection andtearing, and probable trigeminal autonomic cephalagias.

“Other primary headaches” that may be treated by the invention includeprimary cough headache, primary exertional headache, primary headacheassociated with sexual activity, hypnic headache, primary thunderclapheadache, hemicranias continua, and new daily-persistent headache.

“Cluster headache”, also sometimes known as “suicide headache,” isconsidered different from migraine headache. Cluster headache is aneurological disease that involves, as its most prominent feature, animmense degree of pain. “Cluster” refers to the tendency of theseheadaches to occur periodically, with active periods interrupted byspontaneous remissions. The cause of the disease is currently unknown.Cluster headaches affect approximately 0.1% of the population, and menare more commonly affected than women (in contrast to migraine headache,where women are more commonly affected than men).

Sensory disorders that may be treated by the methods and apparatuses ofthe present invention include, but are not limited to, vertigo,dizziness, seasickness, travel sickness cybersickness, sensoryprocessing disorder, hyperacusis, fibromyalgia, neuropathic pain(including, but not limited to, complex regional pain syndrome, phantomlimb pain, thalamic pain syndrome, craniofacial pain, cranialneuropathy, autonomic neuropathy, and peripheral neuropathy (including,but not limited to, entrapment-, heredity-, acute inflammatory-,diabetes-, alcoholism-, industrial toxin-, Leprosy-, Epstein BarrVirus-, liver disease-, ischemia-, and drug-induced neuropathy)),numbness, hemianesthesia, and nerve/root plexus disorders (including,but not limited to, traumatic radiculopathies, neoplasticradiculopathies, vaculitis, and radiation plexopathy).

Motor disorders that may be treated by the method and apparatuses of thepresent invention include, but are not limited to, upper motor neurondisorders such as spastic paraplegia, lower motor neuron disorders suchas spinal muscular atrophy and bulbar palsy, combined upper and lowermotor neuron syndromes such as familial amyotrophic lateral sclerosisand primary lateral sclerosis, and movement disorders (including, butnot limited to, Parkinson's disease, tremor, dystonia, TouretteSyndrome, myoclonus, chorea, nystagmus, spasticity, agraphia,dysgraphia, alien limb syndrome, and drug-induced movement disorders).

Cognitive disorders that may be treated by the method and apparatuses ofthe present invention include, but are not limited to, schizophrenia,addiction, anxiety disorders, depression, bipolar disorder, dementia,insomnia, narcolepsy, autism, Alzheimer's disease, anomia, aphasia,dysphasia, parosmia, spatial neglect, attention deficit hyperactivitydisorder, obsessive compulsive disorder, eating disorders, body imagedisorders, body integrity disorders, post-traumatic stress disorder,intrusive imagery disorders, and mutism.

Metabolic disorders that may be treated by the present invention includediabetes (particularly type II diabetes), hypertension, obesity, etc.

Addiction, addictive disorders, or addictive behavior that may betreated by the present invention includes, but is not limited to,alcohol addiction, tobacco or nicotine addiction (e.g., using thepresent invention as a smoking cessation aid), drug addictions (e.g.,opiates, oxycontin, amphetamines, etc.), food addictions (compulsiveeating disorders), etc.

In some embodiments, the subject has two or more of the aboveconditions, and both conditions are treated concurrently with themethods and systems of the invention. For example, a subject with bothdepression and anxiety (e.g., PTSD) can be treated for both,concurrently, with the methods and systems of the present invention.

Without wishing to be limited to any one theory of the invention, insome embodiments the disorder may be treated through activation of thefastigial nucleus and corresponding mitochondrial activation by themethods described herein. Such disorders, treated in such manner, arereferred to as “mitochondrial disorders” or “mitochondrial dysfunctiondisorders” as discussed further below.

6. Waveform Titration Over Time

As noted above, in the present invention, the waveform stimulus ispreferably titrated over time in the course of treating a particularpatient. Titration can be carried out by any suitable technique.

In one embodiment as shown in FIG. 24, a hierarchical flow of activitiesaround the initiation and continuation of CVS therapy exists. Aqualified physician starts by taking a patient history and establishesthat the patient's disease is appropriate for CVS therapy. Thatinformation is stored in the patient history database module. Thephysician then accesses a library of existing treatment waveformsappropriate to the patient's disease. The physician gathers biometricdata on the patient, which could include height and weight, but also mayinclude results of a direct measurement of the thermal conductionparameters from that patient's ear canal to the inner ear (facilitated,e.g., by an IR sensor that assesses the temperature of the inner earover time as a function of the applied thermal waveform to the earcanal). The physician thus modifies timing parameters, etc. of thedisease-specific thermal waveform to better match the physiology of thepatient.

The physician downloads the CVS prescription to the patient GUIinterface on the CVS treatment unit. This may be done in the physician'sclinic or remotely via a phone, internet, or wireless transfer protocol.The patient GUI interface transfers the prescription data to atime-varying thermal waveform generator, which in turn enables the CVSdevice controller. The CVS device is then activated and will, asfrequently as daily, or even several times a day, enable the patient toreceive a therapeutic treatment. After treatment, the patient will beprompted to input feedback via the patient GUI interface with respect tothe efficacy of treatment. Additionally, the physician may request, at afrequency of his or her choosing, patient data on efficacy and/or sideeffects (examples of which include, but are not limited to, magneticresonance imaging data, EEG data, blood pressure data, pulse data, pulseoximetry data, galvanic skin response data, blood, saliva, or urinechemistry data, nystagmography data, blood glucose data, cerebral bloodflow data (e.g., as determined by any suitable technique such asultrasound or transcranial Doppler sonography) observed parameters suchas facial expressions, verbal or written responses to interviews, etc.).The patient feedback and measurement data is then entered into thepatient history database and accessed by the physician (e.g., to confirmpatient compliance with a particular course of treatment).

Based on the patient's progress with CVS therapy, the physician maychoose to increase the level or duration of CVS stimulus, to decreasethe level or duration of CVS stimulus, to alter the stimulus waveform,combinations of the foregoing, to continue at the current stimulus leveland duration, or stop therapy. Any modifications to the therapyprescription will be input to the patient history database and lead tothe creation of a new prescription for successive patient treatments. Insome embodiments the physician will review the patient's progress anddecide whether to extend the prescription, for example on a 30-daycycle.

In order to properly track a patient's progress with CVS therapy, bothacute and chronic efficacy data will be collected by the treatingphysician. The assessment of efficacy will dictate the course oftherapy. Referring to FIG. 25, and as previously noted, the physicianselects an appropriate therapeutic thermal waveform from a database ofdisease-specific waveforms. That general waveform may be modified bypatient-specific metrics such as gender, age, medical conditions, heightand weight, but also may include results of a direct measurement of thethermal conduction parameters from that patient's ear canal to the innerear (facilitated, e.g., by an IR sensor that assesses the temperature ofthe inner ear over time as a function of the applied thermal waveform tothe ear canal).

As acute treatment of the patient commences, the patient's subjectivefeedback (e.g., verbal reports, automated survey responses to questionsregarding efficacy and/or side-effects, etc.) and the results ofobjective efficacy measurements will be collected by the physician.Objective efficacy metrics include, but are not limited to,nystagmography data, electroencephalography (EEG) data, magneticresonance imaging (MRI) data, pulse data, blood pressure data, galvanicskin response (GSR) data, blood chemistry data (e.g., complete bloodcount, blood sugar levels such as determined by blood A1c levels or theblood A1c test, blood glucose levels, blood cortisol levels, etc.),saliva chemistry data, and urine chemistry data (e.g., urine cortisollevels), etc.). Based on the progress of the patient, optionally withreference to other patients with the same disease state, the physicianmay decide to alter the CVS prescription. In some embodiments,progression to chronic treatment preferably does not occur until thedesired efficacy has been achieved by the physician by iterativeadministration of various acute treatments.

Nystagmography data can be collected by any suitable technique,including but not limited to videonystagmography andelectronystagmography. Various devices for carrying out nystagmographyare known, including but not limited to those described in U.S. Pat.Nos. 7,892,180; 6,800,062; 5,517,021; 5,360,971; 4,474,186; 4,320,768;and 4,155,352.

Once chronic or maintenance treatment commences, the physician canoptionally continue to collect patient feedback (including bothsubjective feedback and objective efficacy metrics) on chronic efficacyand may, at his discretion, collect objective efficacy metrics to ensurethat his therapeutic goals for the patient are maintained.

7. Adjuvant Treatment or Combination Treatments

In some embodiments, the caloric vestibular stimulation is administeredto enhance the efficacy of another treatment or therapeuticintervention, such as a therapeutic drug. The drug (or “active agent”)can be for any condition, including an analgesic for the treatment ofpain (e.g., headache pain), an antidiabetic or hypoglycemic drug for thetreatment of diabetes, or any other active agent such as describedbelow.

As noted above, in some embodiments, instead of an “active agent,” thecaloric vestibular stimulation is administered in combination with orconcurrently with another therapeutic intervention to enhance theefficacy thereof. Examples of such other therapeutic interventionsinclude, but are not limited to, counseling, psychotherapy, cognitivetherapy or the like, electroconvulsive therapy, hydrotherapy, hyperbaricoxygen therapy, electrotherapy and electrical stimulation,transcutaneous electrical nerve stimulation or “TENS” (e.g., for thetreatment of pain such as neuropathic pain), deep brain stimulation(e.g., for the treatment of pain such as neuropathic pain, Parkinson'sdisease, tremor, dystonia, etc.), etc.

Some conditions, such as post-traumatic stress disorder or “PTSD,” canmanifest depression and anxiety as symptoms or aspects thereof, andthose active agents can be used for the treatment of those symptoms inthe methods of the present invention, in like manner as depression oranxiety manifest in the absence of PTSD.

The drug can be an oral drug or orally administered drug, an injectabledrug (e.g., for intramuscular, intraveneous, or subcutaneous injection),a transdermal drug (e.g., delivered by a separate transdermal patch,cream, gel or the like separate from the caloric vestibularstimulation), etc.

Analgesics.

Analgesics (and headache medications) that can be used in carrying outthe combination methods of the present invention include, but are notlimited to: non-steroidal anti-inflammatory drugs (NSAIDs), includingsalicylates (e.g., Aspirin (acetylsalicylic acid), Diflunisal, andSalsalate); propionic acid derivatives (e.g., Ibuprofen, Naproxen,Fenoprofen, Ketoprofen, Flurbiprofen, Oxaprozin, and Loxoprofen), aceticacid derivatives (e.g., Indomethacin, Sulindac, Etodolac, Ketorolac,Diclofenac, and Nabumetone), enolic acid (Oxicam) derivatives (e.g.,Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, and Isoxicam),fenamic acid derivatives (e.g., Mefenamic acid, Meclofenamic acid,Flufenamic acid, and Tolfenamic acid), selective COX-2 inhibitors (e.g.,Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib,and Firocoxib), sulphonanilides (e.g., Nimesulide); opiates and opioids,including natural opiates (e.g., morphine, codeine, and thebaine),Semi-synthetic opioids (e.g., heroin, hydromorphone, hydrocodone,oxycodone, oxymorphone, desomorphine, nicomorphine, dipropanoylmorphine,benzylmorphine and ethylmorphine and buprenorphine) Fully syntheticopioids (e.g., fentanyl, pethidine, methadone, tramadol anddextropropoxyphene) opioid peptides (e.g., endorphins, enkephalins,dynorphins, and endomorphins) tramadol, tapentadol, etc; flupertine;Antihistamines such as hydroxyzine and diphenhydramine; Corticosteroidssuch as prednisone), dexamethasone and methylprednisolone; Depacon;Dihydroergotamine (DHE-45); Ergotamines; Magnesium; Muscle relaxantssuch orphenadrine, baclofen, metaxalone, cyclobenzaprine), carisoprodol,chlorzoxazone, tizanidine and orphenadrine; Phenothiazines such asdroperidol, promethazine, and prochlorperazine; Triptans such assumatriptan, rizatriptan, zolmitriptan, almotriptan, eletriptan,frovatriptan, and naratriptan; Beta-blockers such as propranolol,nadolol, bystolic, atenolol and metroprolol); Botox (botulinum); Calciumchannel blockers such as verapamil and nimodipine; Dopamine reuptakeinhibitors such as as bupropion; Selective serotonin reuptake inhibitors(SSRIs) such as luoxetine, paroxetine, setraline, citalopram andescitalopram; Serotonin and norepinephrine reuptake inhibitors (SNRIs)such as venlafaxine and duloxetine; Specific serotonergic/noradrenergicmedications such as mirtazapine; Tricyclic antidepressants such asamitriptyline, protriptyline, doxepine, desipramine, imipramine,nortriptyline, trimipramine and amitriptyline/chlordiazepoxid; etc. Theforegoing may be used alone or in combination with one another.Additional examples of active compounds that can be used as analgesicsin the methods of the present invention include, but are not limited to,those described in U.S. Pat. Nos. 7,375,106; 7,332,183; 7,030,162;6,926,907; 6,586,458; 6,479,551; 6,451,857; 6,060,499; 5,942,530 and5,872,145, the disclosures of which are incorporated by reference hereinin their entirety.

Active Agents for Headache Treatment.

Examples of headache medications that can be used in carrying out thecombination methods of the present invention include, but are notlimited to: CGRP antagonists in U.S. Pat. No. 8,044,043; CGRPantagonists in combination with one or more agents selected from thegroup consisting of COX-2 inhibitors (as described above), NSAIDs (asdescribed above), acetaminophen, triptans, ergotamine and caffeine forthe treatment of migraine; bicyclic anilide spirolactones in U.S. Pat.No. 8,003,792. Additional agents include: acetaminophen U.S. Pat. No.8,022,095; a 5-HT1_(β)/1_(D) agonist, preferably sumatriptan, and along-acting NSAID, (preferably naproxen) are disclosed for the treatmentof migraine, other preferred long-acting NSAIDs include cyclooxygenase-2inhibitors (COX-2 inhibitors) U.S. Pat. No. 8,022,095. Acetaminophen,propoxyphene, codeine, anti-depressants, MAO inhibitors, anti-epilepticdrugs or barbiturates for the treatment of headaches are disclosed inU.S. Pat. No. 8,008,351; peptidic compounds in U.S. Pat. No. 8,008,351;and antagonists of the ER4 receptor in U.S. Pat. No. 8,013,159. Headachemedicines include but are not limited to analgesics as discussed above.Lists of anti-depressants, anti-epileptic drugs and barbiturates can befound below.

Anti-Diabetic Agents.

Examples of anti-diabetic agents that can be used in carrying out thecombination methods of the present invention include, but are notlimited to, insulin, Biguanides such as Metformin (Glucophage)Phenformin, and Buformin; Thiazolidinediones or “glitazones,” such asrosiglitazone, pioglitazone, and troglitazone; Sulfonylureas such astolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide,glyburide, glimepiride, and gliclazide; Meglitinides such as repaglinideand nateglinide; Alpha-glucosidase inhibitors such as miglitol andacarbose; Incretins or increintin mimetics such as glucagon-likepeptide-1 (GLP-1) and gastric inhibitory peptide; Glucagon-like peptide(GLP) agonists such as Exenatide, Liraglutide, and Taspoglutide;Dipeptidyl peptidase-4 (DPP-4) inhibitors such as vildagliptin,sitagliptin, saxagliptin, and linagliptin; etc. Additional examplesinclude but are not limited to those described in U.S. Pat. Nos.7,939,551 and 7,803,778, the disclosures of which are incorporated byreference herein in their entirety.

Anti-Epileptic Agents.

Examples of anti-epileptic and/or anti-convulsant agents that can beused in carrying out the combination methods of the present inventioninclude, but are not limited to: AMPA antagonists such as AMP-397,E-2007, NS-1209, talampanel, and the like; benzodiazepines such asdiazepam, lorazepam, clonazepam, clobazam, and the like; barbituratessuch as phenobarbital, amobarbital, methylphenobarbital, primidone, andthe like; valproates such as valproic acid, valproate semisodium,valpromide, and the like; GABA agents such as gabapentin, pregabalin,vigabatrin, losigamone, retigabine, rufinamide, SPD-421 (DP-VPA),T-2000, XP-13512, and the like; iminostilbenes such as carbamazepine,oxcarbazepine, and the like; hydantoins such as phenyloin sodium,mephenyloin, fosphenyloin sodium, and the like; NMDA antagonists such asharkoseramide, and the like; sodium channel blockers such as BIA-2093,CO-102862, lamotrigine, and the like; succinimides such as methsuximide,ethosuximide, and the like; and AEDS (anti-epileptic and/oranti-convulsant agents) such as acetazolamide, clomthiazole edisilate,zonisamide, felbamate, topiramate, tiagabine, levetiracetam,briveracetam, GSK-362115, GSK-406725, ICA-69673, CBD cannabisderivative, isovaleramide (NPS-1776), carisbamate, safinamide,seletracetam, soretolide, stiripentol, valrocemide,(2S)-(−)-N-(6-chloro-2,3-dihydro-benzo[1,4]di-oxin-2-ylmethyl)-sulfamide,and the like (U.S. Pat. No. 7,897,636). In addition, the followingclasses of compounds may also be used: GABA prodrugs of gabapentin andpregabalin U.S. Pat. No. 8,048,917; calcium channel antagonists U.S.Pat. No. 8,034,954; sodium channel inhibitors including substitutedbenzenesulfonamides U.S. Pat. No. 8,063,080; substitutedtetrahydropyrrolopyrazines U.S. Pat. No. 8,017,772; substitutedisoquinolines U.S. Pat. No. 8,017,625; sulfonyl hydrazine derivativesU.S. Pat. No. 8,017,628; antiglycolytic compounds such as2-deoxy-D-glucose U.S. Pat. No. 7,795,227; agmatine or agmatine analogsU.S. Pat. No. 7,816,407; benzoazolylpiperazines (U.S. Pat. No.8,008,300); and pyrimido [4,5-D] azepine derivatives as 5-HT_(2c)agonists in U.S. Pat. No. 7,928,099. Lists of calcium channelantagonists can be found below.

Antidepressive Agents.

Examples of anti-depressive agents that can be used in carrying out thecombination methods of the present invention include, but are notlimited to: SSRIs (selective serotonin reuptake inhibitors) thatinclude, without limitation, the following: fluoxetine (e.g., fluoxetinehydrochloride, e.g., Prozac®), fluvoxamine (e.g., fluvoxamine maleate,e.g. Luvox®), paroxetine (e.g., paroxetine hydrochloride, e.g., Paxil®),sertraline (e.g., sertraline hydrochloride, e.g., Zoloft®), citalopram(e.g., citalopram hydrobromide, e.g., Celexa®), duloxetine (e.g.,duloxetine hydrochloride), and venlafaxine (e.g., venlafaxinehydrochloride, e.g., Effexor®). Further SSRIs include those disclosed inU.S. Pat. No. 6,162,805 (U.S. Pat. No. 6,878,732). An antidepressantagent may be selected from the group: norepinephrine reuptakeinhibitors, selective serotonin reuptake inhibitors, monoamine oxidaseinhibitors, reversible monoamine oxidase inhibitors, serotonin andnoradrenaline reuptake inhibitors, corticotropin releasing factor (CRF)antagonists, a-adrenoreceptor antagonists and atypical antidepressants,as a combined preparation for simultaneous, separate or sequential usein the treatment or prevention of depression and/or anxiety U.S. Pat.No. 6,117,855. Additional classes of agents include the tricyclicantidepressants such as amitriptyline, imipramine, doxepin, maprotiline,protriptyline, nortriptyline, desimipramine, clomipramine, trimipramineU.S. Pat. No. 6,127,385; tetracyclics such as dibenzoxepinon anddibenzothiepino-pyridinol or pyrrotol derivatives U.S. Pat. No.4,977,158; and atypical antidepressants such as nefazodone or buproprion(should be spelled as bupropion) U.S. Pat. No. 6,127,385. Furtherclasses are represented by(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane U.S. Pat. No.6,372,919; N¹-propargylhydrazines, N²-proargylhydrazines and theiranalogs U.S. Pat. No. 6,060,516 and NK-1 receptor antagonists U.S. Pat.No. 6,114,315. NK-1 receptor antagonists include MK-869 and CP-122,721U.S. Pat. No. 8,071,778. Benzoazolylpiperazines have been disclosed inU.S. Pat. No. 8,008,300; thienopyridones as 5HT receptor agonists andpartial agonists in U.S. Pat. No. 7,982,040; spirocyclic heterocyclicderivatives in U.S. Pat. No. 8,071,611; and pyrimido [4,5-D] azepinederivatives are disclosed as 5-HT_(2c) agonists in U.S. Pat. No.7,928,099. Useful anti-depressant agents include but are not limited to,amitriptyline, clomipramine, doxepine, imipramine, trimipramine,amoxapine, desipramine, maprotiline, nortriptyline, protripyline,fluoxetine, fluvoxamine, paroxetine, setraline, venlafaxine, bupropion,nefazodone, trazodone, pheuelzine, tranylcypromine and selegiline U.S.Pat. No. 6,372,919. Anti-depressants of current interest includezimeldine, bupropion and nomifensine U.S. Pat. No. 7,982,040.Antidepressants, such as, for example, agomelatine, amitriptyline,amoxapine, bupropion, citalopram, clomipramine desipramine, doxepin,duloxetine, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine,ipsapirone, isocarboxazid, maprotiline, mirtazepine, nortriptyline,nefazodone paroxetine, phenelzine, protriptyline, ramelteon, reboxetine,robalzotan, selegiline, sertraline, sibutramine, thionisoxetine,tranylcypromaine, trazodone, trimipramine, venlafaxine, and equivalentsand pharmaceutically active isomer(s) and metabolite(s) thereof, (U.S.Pat. No. 8,063,215).

Antipsychotic Agents:

Examples of antipsychotic agents that can be used in carrying out thecombination methods of the present invention include, but are notlimited to: amisulpride, aripirazole, asenapine, benzisoxidil,bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapines,dibenzapine, divalproex, droperidol, fluphenazine, haloperidol,iloperidone, loxapine, mesoridazine, molindone, olanzapine,paliperidone, perphenazine, phenothiazine, phenylbutylpiperidine,pimozide, prochlorperazine, quetiapine, risperidone, sertindole,sulpiride, suproclone, thioridazine, thiothixene, trifluoperazine,trimetozine, valproate, valproic acid, zotepine, ziprasidone, andequivalents and pharmaceutically active isomer(s) and metabolite(s)thereof (U.S. Pat. No. 8,063,215).

Anxiolytic Agents.

Examples of anxiolytic agents that can be used in carrying out thecombination methods of the present invention include, but are notlimited to: benzodiazepines, such as alprazolam, chlordiazepoxide,clonazepam, clorazepate, diazepam, halazepam, lorazepam, oxazepam, andprazepam; non-benzodiazepine agents, such as buspirone; andtranquilizers such as barbiturates U.S. Pat. No. 6,372,919.Pyrimido[4,5-D] azepine derivatives as 5-HT2c agonists in U.S. Pat. No.7,928,099. Anxiolytics, such as, for example, alnespirone, azapirones,benzodiazepines, and barbiturates, such as, for example, adinazolam,alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone,clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam,estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam,lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam,quazepam, reclazepam, suriclone, tracazolate, trepipam, temazepam,triazolam, uldazepam, zolazepam, and equivalents and pharmaceuticallyactive isomer(s) and metabolite(s) thereof U.S. Pat. No. 8,063,215.Additional classes of anxiolytics include substitutedtetrahydropyrrolopyrazines U.S. Pat. No. 8,017,772; NK-1 receptorantagonists U.S. Pat. No. 6,114,315; N¹-propargylhydrazines,N²-proargylhydrazines and their analogs U.S. Pat. No. 6,060,516;benzoazolylpiperazines in U.S. Pat. No. 8,008,300; and thienopyridonesin U.S. Pat. No. 7,982,040 (as serotonin receptor modulators).

Active Agents for Treating Bipolar Disorder.

Examples of drugs used for the treatment of bipolar disorder that can beused in carrying out the combination methods of the present inventioninclude, but are not limited to: SSRIs in combination withantipsychotics such as fluoxetine plus olanzapine U.S. Pat. No.8,071,778; spirocyclic heterocyclic derivatives in U.S. Pat. No.8,071,611; 4-piperazin-1-yl-4-benzo[B]thiophenes for the treatment ofbipolar I type disorder and bipolar II type disorder U.S. Pat. No.8,071,600; 3,9-diazabicyclo[3,3,1]nonanes in U.S. Pat. No. 8,071,598;7-cycloalkylaminoquinolines are reported as GSK-3 inhibitors in U.S.Pat. No. 8,071,591; 1,2-disubstituted heterocyclic compounds aredisclosed as phosphodiesterase 10 inhibitors in U.S. Pat. No. 8,071,595;and pyridine-alkynyl compounds are disclosed in U.S. Pat. No. 8,058,292.Lists of SSRIs and antipsychotics can be found above.

Mood Stabilizer Active Agents.

Examples of drugs used to stabilize mood that can be used in carryingout the combination methods of the present invention include, but arenot limited to: carbamazepine, divalproex, gabapentin, lamotrigine,lithium, olanzapine, oxycarbazepine, quetiapine, valproate, valproicacid, verapamil, and equivalents and pharmaceutically active isomer(s)and metabolite(s) thereof (U.S. Pat. No. 8,063,215).

Anti-Insomnia (Including Sedative Hypnotic) Active Agents

Examples of insomnia and sedative hypnotic agents that can be used incarrying out the combination methods of the present invention include,but are not limited to: agomelatine, allobarbital, alonimid,amobarbital, benzoctamine, butabarbital, capuride, chloral hydrate,clonazepam, chlorazepate, cloperidone, clorethate, dexclamol, estazolam,eszopiclone, ethchlorvynol, etomidate, flurazepam, glutethimide,halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital,methaqualone, midaflur, midazolam, nisobamate, pagoclone, pentobarbital,perlapine, phenobarbital, propofol, quazepam, ramelteon, roletamide,suproclone, temazepam, triazolam, triclofos, secobarbital, zaleplon,zolpidem, zopiclone and equivalents and pharmaceutically activeisomer(s) and metabolite(s) thereof (U.S. Pat. No. 8,063,215).

Active Agents for Treating Stroke.

Examples of agents useful for the treatment of stroke that can be usedin carrying out the combination methods of the present inventioninclude, but are not limited to: abciximab, activase, NXY-059,citicoline, crobenetine, desmoteplase, repinotan, traxoprodil, andequivalents and pharmaceutically active isomer(s) and metabolite(s)thereof (U.S. Pat. No. 8,063,215).

Active Agents for Treating Substance Abuse Disorders, Dependence andWithdrawal.

Examples of agents used to treat substance abuse disorders, dependenceand withdrawal that can be used in carrying out the combination methodsof the present invention include, but are not limited to: nicotinereplacement therapies (i.e., gum, patches, and nasal spray);nicotinergic receptor agonists, partial agonists, and antagonists, (e.g.varenicline); acomprosate, bupropion, clonidine, disulfuram, methadone,naloxone, naltrexone, and equivalents and pharmaceutically activeisomer(s) and metabolite(s) thereof (U.S. Pat. No. 8,063,215).

Active Agents for Treating ADHD

Examples of agents used for the treatment of AHDH that can be used incarrying out the combination methods of the present invention include,but are not limited to: amphetamine, methamphetamine, dextroamphetamine,atomoxetine, methylphenidate, dexmethylphenidate, modafinil, andequivalents and pharmaceutically active isomer(s) and metabolite(s)thereof (U.S. Pat. No. 8,063,215).

Active Agents for Treating Alzheimer's Disease.

Examples of agents that can be used for the treatment of Alzheimer'sthat can be used in carrying out the combination methods of the presentinvention include, but are not limited to: donepezil, galantamine,memantine, rivastigmine, tacrine, and equivalent and pharmaceuticallyactive isomer(s) and metabolite(s) thereof (U.S. Pat. No. 8,063,215).

Active Agents for Treating Parkinson's Disease and ExtrapyramidalSymptoms.

Examples of agents that can be used for the treatment of Parkinson's andagents for the treatment of extrapyramidal symptoms that can be used incarrying out the combination methods of the present invention include,but are not limited to: levodopa, carbidopa, amantadine, pramipexole,ropinirole, pergolide, cabergoline, apomorphine, bromocriptine, MAOBinhibitors (i.e. selegine and rasagiline), COMT inhibitors (i.e.entacapone and tolcapone), alpha-2 inhibitors, anticholinergics (i.e.,benztropine, biperiden, orphenadrine, procyclidine, andtrihexyphenidyl), dopamine reuptake inhibitors, NMDA antagonists,Nicotine agonists, Dopamine agonists, and inhibitors of neuronal nitricoxide synthase, and equivalents and pharmaceutically active isomer(s)and metabolite(s) thereof (U.S. Pat. No. 8,063,215).

Active Agents for Treating Neuropathic Pain.

Examples of agents used for the treatment of neuropathic pain that canbe used in carrying out the combination methods of the present inventioninclude, but are not limited to: gabapentin, lidoderm, pregablin, andequivalents and pharmaceutically active isomer(s) and metabolite(s)thereof (U.S. Pat. No. 8,063,215).

Active Agents for Treating Nociceptive Pain.

Examples of agents used for the treatment of nociceptive pain that canbe used in carrying out the combination methods of the present inventioninclude, but are not limited to: celecoxib, codeine, diclofenac,etoricoxib, fentanyl, hydrocodone, hydromorphone,levo-alpha-acetylmethadol, loxoprofen, lumiracoxib, meperidine,methadone, morphine, naproxen, oxycodone, paracetamol, propoxyphene,rofecoxib, sufentanyl, valdecoxib, and equivalents and pharmaceuticallyactive isomer(s) and metabolite(s) thereof (U.S. Pat. No. 8,063,215).

Active Agents for Treating Obesity.

Examples of agents used for the treatment of obesity that can be used incarrying out the combination methods of the present invention include,but are not limited: anti-obesity drugs that affect energy expenditure,glycolysis, gluconeogenesis, glucogenolysis, lipolysis, lipogenesis, fatabsorption, fat storage, fat excretion, hunger and/or satiety and/orcraving mechanisms, appetite/motivation, food intake, and G-I motility;very low calorie diets (VLCD); and low-calorie diets (LCD) (U.S. Pat.No. 8,063,215).

Active Agents for Treating Obesity Associated Disorders

Examples of agents useful for the treatment of obesity associateddisorders that can be used in carrying out the combination methods ofthe present invention include, but are not limited to: for example,biguanide drugs, insulin (synthetic insulin analogues) and oralantihyperglycemics (these are divided into prandial glucose regulatorsand alpha-glucosidase inhibitors), PPAR modulating agents, such as, forexample, PPAR alpha and/or gamma agonists; sulfonylureas;cholesterol-lowering agents, such as, for example, inhibitors of HMG-CoAreductase (3-hydroxy-3-methylglutaryl coenzyme A reductase); aninhibitor of the ileal bile acid transport system (IBAT inhibitor); abile acid binding resin; bile acid sequestering agent, such as, forexample, colestipol, cholestyramine, or cholestagel; a CETP (cholesterylester transfer protein) inhibitor; a cholesterol absorption antagonist;a MTP (microsomal transfer protein) inhibitor; a nicotinic acidderivative, including slow release and combination products; aphytosterol compound; probucol; an anti-coagulant; an omega-3 fattyacid; an anti-obesity therapy, such as, for example, sibutramine,phentermine, orlistat, bupropion, ephedrine, and thyroxine; anantihypertensive, such as, for example, an angiotensin converting enzyme(ACE) inhibitor, an angiotensin II receptor antagonist, an adrenergicblocker, an alpha adrenergic blocker, a beta adrenergic blocker, a mixedalpha/beta adrenergic blocker, an adrenergic stimulant, calcium channelblocker, an AT-1 blocker, a saluretic, a diuretic, and a vasodilator; amelanin concentrating hormone (MCH) modulator; an NPY receptormodulator; an orexin receptor modulator; a phosphoinositide-dependentprotein kinase (PDK) modulator; modulators of nuclear receptors, suchas, for example, LXR, FXR, RXR, GR, ERRα, β, PPARα, β, γ and RORalpha; amonoamine transmission-modulating agent, such as, for example, aselective serotonin reuptake inhibitor (SSRI), a noradrenaline reuptakeinhibitor (NARI), a noradrenaline-serotonin reuptake inhibitor (SNRI), amonoamine oxidase inhibitor (MAOI), a tricyclic antidepressive agent(TCA), a noradrenergic and specific serotonergic antidepressant (NaSSA);a serotonin receptor modulator; a leptin/leptin receptor modulator; aghrelin/ghrelin receptor modulator; a DPP-IV inhibitor; and equivalentsand pharmaceutically active isomer(s), metabolite(s), andpharmaceutically acceptable salts, solvates, and prodrugs thereof (U.S.Pat. No. 8,063,215). Lists of anti-hypertensive agents andcardiovascular agents can be found below. Lists of SSRIs andantidepressants can be found above.

Anti-Hypertensive Agents

Examples of anti-hypertensive agents that can be used in carrying outthe combination methods of the present invention include, but are notlimited to: vasodilators such as prostacyclin, epoprostenol, andsildenafil; endothelin receptor antagonists such as bosentan; calciumchannel blockers such as amlodipine, diltiazem, and nifedipine;anticoagulants such as warfarin; and diuretics. Treatment of PH has alsobeen carried out using oxygen therapy; and lung and/or hearttransplantation U.S. Pat. No. 8,071,557. Carbonic anhydrase inhibitorsare disclosed in U.S. Pat. No. 8,071,557 while urotensin II receptorantagonists for the treatment of hypertension are disclosed in U.S. Pat.No. 8,067,601.1-[2-(4-benzyl-4-hydroxy-piperdin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-ureasalts (urotensin II receptor antagonists) may also be used incombination with one or more other therapeutically useful substancese.g. with α- and β-blockers like phentolamine, phenoxybenzamine,atenolol, propranolol, timolol, metoprolol, carteolol, carvedilol, etc.;with vasodilators like hydralazine, minoxidil, diazoxide, flosequinan,etc.; with calcium-antagonists like diltiazem, nicardipine, nimodipine,verapamil, nifedipine, etc.; with angiotensin convertingenzyme-inhibitors like cilazapril, captopril, enalapril, lisinopriletc.; with potassium channel activators like pinacidil, chromakalim,etc.; with angiotensin receptor antagonists like losartan, valsartan,candesartan, irbesartan, eprosartan, telmisartan, and tasosartan, etc.;with diuretics like hydrochlorothiazide, chlorothiazide, acetolamide,bumetanide, furosemide, metolazone, chlortalidone, etc.; withsympatholytics like methyldopa, clonidine, guanabenz, reserpine, etc.;with endothelin receptor antagonists like bosentan, clazosentan,tezosentan, darusentan, atrasentan, enrasentan, or sitaxsentan, etc.;with anti-hyperlipidemic agents like lovastatin, pravastatin,fluvastatin, atorvastatin, cerivastatin, simvastatin, etc.; and othertherapeutics which serve to treat high blood pressure, vascular diseaseor other disorders listed above U.S. Pat. No. 8,067,601.Antihypertensives such as, for example, an angiotensin converting enzyme(ACE) inhibitor, an angiotensin II receptor antagonist, an adrenergicblocker, an alpha adrenergic blocker, a beta adrenergic blocker, a mixedalpha/beta adrenergic blocker, an adrenergic stimulant, calcium channelblocker, an AT-1 blocker, a saluretic, a diuretic, and a vasodilator aredisclosed in U.S. Pat. No. 8,063,215. Examples of the antihypertensivedrugs include angiotensin converting enzyme inhibitors (such ascaptopril, alacepril, lisinopril, imidapril, quinapril, temocapril,delapril, benazepril, cilazapril, trandolapril, enalapril, ceronapril,fosinopril, imadapril, mobertpril, perindopril, ramipril, spirapril, andrandolapril), angiotensin II antagonists (such as losartan, candesartan,valsartan, eprosartan, and irbesartan), calcium channel blocking drugs(such as aranidipine, efonidipine, nicardipine, bamidipine, benidipine,manidipine, cilnidipine, nisoldipine, nitrendipine, nifedipine,nilvadipine, felodipine, amlodipine, diltiazem, bepridil, clentiazem,phendilin, galopamil, mibefradil, prenylamine, semotiadil, terodiline,verapamil, cilnidipine, elgodipine, isradipine, lacidipine,lercanidipine, nimodipine, cinnarizine, flunarizine, lidoflazine,lomerizine, bencyclane, etafenone, and perhexyline), β-adrenalinereceptor blocking drugs (propranolol, pindolol, indenolol, carteolol,bunitrolol, atenolol, acebutolol, metoprolol, timolol, nipradilol,penbutolol, nadolol, tilisolol, carvedilol, bisoprolol, betaxolol,celiprolol, bopindolol, bevantolol, labetalol, alprenolol, amosulalol,arotinolol, befunolol, bucumolol, bufetolol, buferalol, buprandolol,butylidine, butofilolol, carazolol, cetamolol, cloranolol, dilevalol,epanolol, levobunolol, mepindolol, metipranolol, moprolol, nadoxolol,nevibolol, oxprenolol, practol, pronetalol, sotalol, sufinalol,talindolol, tertalol, toliprolol, xybenolol, and esmolol), α-receptorblocking drugs (such as amosulalol, prazosin, terazosin, doxazosin,bunazosin, urapidil, phentolamine, arotinolol, dapiprazole, fenspiride,indoramin, labetalol, naftopidil, nicergoline, tamsulosin, tolazoline,trimazosin, and yohimbine), sympathetic nerve inhibitors (such asclonidine, guanfacine, guanabenz, methyldopa, and reserpine),hydralazine, todralazine, budralazine, and cadralazine U.S. Pat. No.8,044,198.

Cardiovascular Agents

Examples of cardiovascular agents that can be used in carrying out thecombination methods of the present invention include, but are notlimited to: vasodilators, for example, hydralazine; angiotensinconverting enzyme inhibitors, for example, captopril; anti-anginalagents, for example, isosorbide nitrate, glyceryl trinitrate andpentaerythritol tetranitrate; anti-arrhythmic agents, for example,quinidine, procainaltide and lignocaine; cardioglycosides, for example,digoxin and digitoxin; calcium antagonists, for example, verapamil andnifedipine; diuretics, such as thiazides and related compounds, forexample, bendrofluazide, chlorothiazide, chlorothalidone,hydrochlorothiazide and other diuretics, for example, fursemide andtriamterene, and sedatives, for example, nitrazepam, flurazepam anddiazepam. Other exemplary cardiovascular agents include, for example, acyclooxygenase inhibitor such as aspirin or indomethacin, a plateletaggregation inhibitor such as clopidogrel, ticlopidene or aspirin,fibrinogen antagonists or a diuretic such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchiorthiazide, trichloromethiazide,polythiazide or benzthiazide as well as ethacrynic acid tricrynafen,chlorthalidone, furosemide, musolimine, bumetanide, triamterene,amiloride and spironolactone and salts of such compounds, angiotensinconverting enzyme inhibitors such as captopril, zofenopril, fosinopril,enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril,ramipril, lisinopril, and salts of such compounds, angiotensin IIantagonists such as losartan, irbesartan or valsartan, thrombolyticagents such as tissue plasminogen activator (tPA), recombinant tPA,streptokinase, urokinase, prourokinase, and anisoylated plasminogenstreptokinase activator complex (APSAC, Eminase, Beecham Laboratories),or animal salivary gland plasminogen activators, calcium channelblocking agents such as verapamil, nifedipine or diltiazem, thromboxanereceptor antagonists such as ifetroban, prostacyclin mimetics, orphosphodiesterase inhibitors. Yet other exemplary cardiovascular agentsinclude, for example, vasodilators, e.g., bencyclane, cinnarizine,citicoline, cyclandelate, cyclonicate, ebumamonine, phenoxezyl,flunarizine, ibudilast, ifenprodil, lomerizine, naphlole, nikamate,nosergoline, nimodipine, papaverine, pentifylline, nofedoline, vincamin,vinpocetine, vichizyl, pentoxifylline, prostacyclin derivatives (such asprostaglandin E1 and prostaglandin I2), an endothelin receptor blockingdrug (such as bosentan), diltiazem, nicorandil, and nitroglycerin U.S.Pat. No. 8,044,198.

Anti-Arrhythmia Agents

Examples of anti-arrhythmia agents that can be used in carrying out thecombination methods of the present invention include, but are notlimited to: four main groups according to their mechanism of action:type I, sodium channel blockade; type II, beta-adrenergic blockade; typeIII, repolarization prolongation; and type IV, calcium channel blockade.Type I anti-arrhythmic agents include lidocaine, moricizine, mexiletine,tocamide, procainamide, encamide, flecanide, tocamide, phenyloin,propafenone, quinidine, disopyramide, and flecamide. Type IIanti-arrhythmic agents include propranolol and esmolol. Type IIIincludes agents that act by prolonging the duration of the actionpotential, such as amiodarone, artilide, bretylium, clofilium,isobutilide, sotalol, azimilide, dofetilide, dronedarone, ersentilide,ibutilide, tedisamil, and trecetilide. Type IV anti-arrhythmic agentsinclude verapamil, diltaizem, digitalis, adenosine, nickel chloride, andmagnesium ions U.S. Pat. No. 8,044,198. Lists of beta-adrenergicblockers and calcium blockers can be found above.

Antianginal Agents

Examples of antianginal agents that can be used in carrying out thecombination methods of the present invention include, but are notlimited to: nitrate drugs (such as amyl nitrite, nitroglycerin, andisosorbide), O-adrenaline receptor blocking drugs (such as propranolol,pindolol, indenolol, carteolol, bunitrolol, atenolol, acebutolol,metoprolol, timolol, nipradilol, penbutolol, nadolol, tilisolol,carvedilol, bisoprolol, betaxolol, celiprolol, bopindolol, bevantolol,labetalol, alprenolol, amosulalol, arotinolol, befunolol, bucumolol,bufetolol, buferalol, buprandolol, butylidine, butofilolol, carazolol,cetamolol, cloranolol, dilevalol, epanolol, levobunolol, mepindolol,metipranolol, moprolol, nadoxolol, nevibolol, oxprenolol, practol,pronetalol, sotalol, sufinalol, talindolol, tertalol, toliprolol, andxybenolol), calcium channel blocking drugs (such as aranidipine,efonidipine, nicardipine, bamidipine, benidipine, manidipine,cilnidipine, nisoldipine, nitrendipine, nifedipine, nilvadipine,felodipine, amlodipine, diltiazem, bepridil, clentiazem, phendiline,galopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil,cilnidipine, elgodipine, isradipine, lacidipine, lercanidipine,nimodipine, cinnarizine, flunarizine, lidoflazine, lomerizine,bencyclane, etafenone, and perhexyline) trimetazidine, dipyridamole,etafenone, dilazep, trapidil, nicorandil, enoxaparin, and aspirin U.S.Pat. No. 8,044,198.

Active Agents Used for Treating Traumatic Brain Injury, NeuroprotectiveAgents, Cerebral Protecting Agents.

Examples of agents used as a result of traumatic brain injury,neuroprotective agents and/or cerebral protecting agents that can beused in carrying out the combination methods of the present inventioninclude, but are not limited to: anesthetics such as phenol derivativesdisclosed in U.S. Pat. No. 8,071,818; neuroprotective agents such asGly-Pro-Glu (GPE) and analogs, cyclic Pro-Gly (“cPG”), diketopiperazineanalogs of thyrotropin-releasing hormone (TRH), and noveldiketopiperazines (U.S. Pat. No. 8,067,425) and disclosures of which areincorporated by reference herein in their entirety. In U.S. Pat. No.8,063,215, cyclopropyl amides are targeted at the histamine H3 receptoras potential treatments for traumatic brain injury. In U.S. Pat. No.8,071,602, SA 4503, diamines, piperazine derivatives, homopiperazinesare incorporated by reference. In addition, 1,4-piperidine andpiperazine derivatives with high affinity for sigma-1 receptors aredisclosed (U.S. Pat. No. 8,071,602). In U.S. Pat. No. 8,067,425, noveldiketopiperazines structurally related to cPG are disclosed. Additionalneuroprotective agents, include for example, growth factors andassociated derivatives (insulin-like growth factor-I [IGF-I],insulin-like growth factor-I1 [IGF-II], transforming growth factor-#1,activin, growth hormone, nerve growth factor, growth hormone bindingprotein, IGF-binding proteins [especially IGFBP-3], basic fibroblastgrowth factor, acidic fibroblast growth factor, the hst/Kfgk geneproduct, FGF-3, FGF-4, FGF-6, keratinocyte growth factor,androgen-induced growth factor. Additional members of the FGF familyinclude, for example, int-2, fibroblast growth factor homologousfactor-1 (FHF-1), FHF-2, FHF-3 and FHF-4, karatinocyte growth factor 2,glial-activating factor FGF-10 and FGF-16, ciliary neurotrophic factor,brain derived growth factor, neurotrophin 3, neurotrophin 4, bonemorphogenetic protein 2 [BMP-2], glial-cell line derived neurotrophicfactor, activity-dependant neurotrophic factor, cytokine leukaemiainhibiting factor, oncostatin M, interleukin α-, β-, γ-, or consensusinterferon, and TNF-α. Other forms of neuroprotective therapeutic agentsinclude, for example, clomethiazole; kynurenic acid, Semax, tacrolimus,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-pro-panol,andrenocorticotropin-(4-9) analogue [ORG 2766] and dizolcipine [MK-801],selegiline; glutamate antagonists such as, NP51506, GV1505260, MK-801,GV150526; AMPA antagonists such as2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070and LY300164; anti-inflammatory agents directed against the addressinMAd-CAM-1 and/or its integrin α4 receptors (α4β1 and α4β7), such asanti-MAdCAM-1mAb MECA-367 (ATCC accession no. HB-9478) U.S. Pat. No.8,967,425. Examples of cerebral protecting drugs include radicalscavengers (such as edaravone, vitamin E, and vitamin C), glutamateantagonists, AMPA antagonists, kainate antagonists, NMDA antagonists,GABA agonists, growth factors, opioid antagonists, phosphatidylcholineprecursors, serotonin agonists, Na⁺/Ca⁺² channel inhibitory drugs, andK⁺ channel opening drugs U.S. Pat. No. 8,044,198.

Active Agents for Treating Premenstrual Syndrome and PremenstrualDysphoric Disorder.

Examples of agents used to treat premenstrual syndrome and/orpremenstrual dysphoric disorder that can be used in carrying out thecombination methods of the present invention include, but are notlimited to: Zoloft U.S. Pat. No. 8,012,958; tachykinin and serotoninmodulators U.S. Pat. No. 8,071,778 and its disclosures of which areincorporated by reference herein in their entirety; progestagens U.S.Pat. No. 8,063,037 and its disclosures of which are incorporated byreference herein in their entirety; controlled release compositionscomprising a LH-RH derivative U.S. Pat. No. 8,067,030; selectiveandrogen modulators that may be employed alone or in combination withother therapeutic agents. By way of non-limiting example, the compoundsof this invention can be used in combination with anti-lipidemics(statins, fibrates, omega-3 oils, niacinates and the like), boneanti-resorptives (bisphosphonates, estrogens, selective estrogenreceptor modulators (SERMs), calcitonin, and the like), bone anabolicagents (PTH and fragments e.g teriparatide, PTHRP and analogues e.g.Ba058), anti-diabetics (e.g. insulin sensitizers, glucose absorption andsynthesis inhibitors (e.g. metformin)), anti-anxiety agents,antidepressants, anti-obesity agents, contraceptive agents, anti-canceragents, PPARy agonists (e.g. pioglitazone), and the like U.S. Pat. No.8,067,448. Additional agents for the treatment of premenstrual syndromeand/or premenstrual dysphoric disorder include: diuretics includingbumetanide, ethacrynic acid, furosemide, muzolimine, spironolactone,torsemide, triamterene, tripamide HG 9928, and HG 9719; Ginkgo extractsU.S. Pat. No. 7,923,045; sirtuin modulating compounds U.S. Pat. No.8,044,198. Diuretics also include compounds such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchiorthiazide, trichloromethiazide,polythiazide or benzthiazide as well as ethacrynic acid tricrynafen,chlorthalidone, furosemide, musolimine, bumetanide, triamterene,amiloride and spironolactone and salts of such compounds; thiazidediuretics (such as hydrochlorothiazide, methyclothiazide,trichlormethiazide, benzylhydrochlorothiazide, and penflutizide), loopdiuretics (such as furosemide, etacrynic acid, bumetanide, piretanide,azosemide, and torasemide), K⁺ sparing diuretics (spironolactone,triamterene, and potassium canrenoate), osmotic diuretics (such asisosorbide, D-mannitol, and glycerin), nonthiazide diuretics (such asmeticrane, tripamide, chlorthalidone, and mefruside), and acetazolamideU.S. Pat. No. 8,044,198. Additional agents include α_(1D) adrenergicreceptor antagonists U.S. Pat. No. 7,985,863; supplements andDL-phenylalanine U.S. Pat. No. 7,871,609. Analgesics, anti-anxiety(anxiolytics), anti-diabetic agents, anti-obesity and antidepressants asdescribed above.

Transcutaneous Electrical Nerve Stimulation.

Examples of transcutaneous electrical nerve stimulation (TENS) methods,systems and devices that can be used in combination with the caloricvestibular stimulation methods, systems and devices described hereininclude, but are not limited to, those described in U.S. Pat. Nos.7,706,885; 7,187,977; 6,161,044; 4,989,605; and 4,723,552.

Deep Brain Stimulation.

Examples of deep brain stimulation methods, systems and devices that canbe used in combination with the caloric vestibular stimulation methods,systems and devices described herein include, but are not limited to,those described in U.S. Pat. Nos. 8,032,231; 7,979,129; 7,957,808;7,833,191; 7,369,899; and 5,938,688.

The present invention is explained in greater detail in the followingnon-limiting Examples.

Example 1 Long Duration Square Wave Administration

A male subject in his forties and good health, naïve to CVS treatment,was administered cold caloric vestibular stimulation to his right ear ina square waveform pattern. The pattern was of cooling to 10 degreesCentigrade (as compared to normal body temperature of about 37 degreesCentigrade) as a “step” function or “square wave” with one symmetricsquare wave being delivered for a time period of 20 minutes. The subjectwas observed by others to be slurring his words, and was asked to remainseated for a time of two hours following the treatment session as aprecaution. Otherwise, no long-term deleterious effects were observed.

Example 2 Sawtooth Wave Administration

The same subject described in EXAMPLE 1 was subsequently treated byadministering cold caloric vestibular stimulation to the right ear in asawtooth waveform pattern of cooling to 20 degrees Centigrade (ascompared to normal body temperature of about 37 degrees Centigrade) in asymmetric sawtooth waveform pattern, without gaps, at a frequency of onecycle or waveform every five minutes, for a total duration ofapproximately 10 minutes and a delivery of a first and second waveform.Unlike the situation with the square wave pattern described in Example1, the subject continued to perceive the temperature cycling up anddown.

Example 3 Maximum Waveform Amplitude

The same subject described in Examples 1-2 was administered cold caloricvestibular stimulation to the right ear as a sawtooth cooling waveformat different amplitudes in a titration study. A maximum perceivedsensation of cyclic cooling was perceived at a peak amplitude of about17 degrees Centigrade (or cooling from normal body temperature to atemperature of about 20 degrees Centigrade). Cooling beyond this did notlead to additional gains in the sensation of cyclic cooling perceived bythe subject.

Example 4 Minimum Waveform Amplitude

Modeling of the human vestibular system indicates that the cupula (thestructure within the semicircular canals pushed by the movement of fluidtherein and which contain hair cells that convert the mechanicaldistortion to electrical signals in the vestibular nerve), is stimulatedby caloric vestibular stimulation at chilling temperatures of 5 or 7degrees Centigrade below body temperature.

Example 5 Maximum Waveform Frequency

Modeling of the human vestibular system indicates that a slew ratefaster than 20 degrees Centigrade per minute (which would enable one 20degree Centigrade waveform every two minutes) is not useful because thehuman body cannot adapt to temperature changes at a more rapid rate.While maximum frequency is dependent in part on other factors such aswaveform amplitude, a maximum frequency of about one cycle every one totwo minutes is indicated.

Example 6 Minimum Waveform Frequency

Modeling of the human vestibular system indicates that a continuous,time-varying waveform is most effective in stimulating the vestibularsystem, as stagnation and adaptation of the cupula is thereby minimized.While minimum frequency is dependent in part on other factors such asthe waveform amplitude, a minimum frequency of about one cycle every tento twenty minutes is indicated.

Example 7 Treatment Session Duration

To permit delivery of at least a first and second waveform, a durationof at least one or two minutes is preferred. As noted above and below,results have been reported by patients with treatment durations of tenand twenty minutes. Hence, as a matter of convenience, a treatmentsession duration of not more than 30 or 40 minutes is preferred (thoughlonger sessions may be desired for some conditions, such as acute caresituations).

Example 8 Treatment of Migraine Headache with Sawtooth Waveforms

A female patient in her early fifties with a long standing history ofmigraine suffered an acute migraine episode with symptoms that consistedof a pounding headache, nausea, phonophobia, and photophobia. Right earcold caloric vestibular stimulation was performed using the sawtoothwaveform, essentially as described in Example 2 above, with atemperature maximum of 17 degrees (chilling from body temperature) for10 minutes (for a total delivery of two cycles). At the conclusion ofthe treatment the patient reported that her headache and associatedsymptoms were no longer present. At a reassessment one day later, thepatient reported that the headache had not returned.

Example 9 Treatment of Diabetes with Sawtooth Waveforms

The same subject described in examples 1-3 suddenly developed an episodeof extreme urination (10 liters per day), thirst for ice water, andassociated fatigue. Urinary testing suggested the onset of diabetesmellitus, for which there was strong family history.

The patient's initial weight as taken at his primary care physicianindicated a recent 20 pound weight loss. The first attempt to obtain aglucose reading from the patient resulted in an out of range result(this result typically occurs with glucose levels in excess of 600mg/dl). The patient was hospitalized and received hydration and IVinsulin therapy. The patient's first glucose level after this treatmentwas 700 mg/dl. The glucose level were brought down to approximately 350and treatment with an oral antihyperglycemic agent was initiated.

Follow-up care after hospital discharge with the subject's primary carephysician. expanded the oral antihyperglycemic agent therapy to includeboth metformin and JANUVIA™ sitagliptin. In addition, a strict exerciseprogram of 30-45 minutes 5 to 6 days per week and diet control wereinstituted. Daily glucose levels via finger stick were taken 2 to 3times per day.

At this point the patient's baseline hemoglobin A1c (Hb A1c) level was9.8%, as compared to normal levels of 5 to 6%.

The patient then began daily treatment with caloric vestibularstimulation. The treatment was carried out for a time of ten minutes,once a day for about a month, after which the treatment was continuedtwo to three times a week for three additional months (with eachtreatment session being about 10 minutes in duration). The caloricvestibular stimulation was delivered to the patient's right ear, as asawtooth cooling waveform as described in Example 2. At the conclusionof these treatments, the patient's HB A1c level was 5.3%. As a result,the patient was removed from all hypoglemic agents.

Most oral antihyperglycemic agents lower a patient's Hb A1c level byapproximately 1 to 2% (see generally S. Inzucchi, Oral AntihyperglycemicTherapy for Type 2 Diabetes, JAMA 287, 360-372 (Jan. 16, 2002)). Incontrast, this patient's initial value was 9.5, and dropped to 5.3.

Example 10 Alternate Waveform Shapes

The sawtooth waveform described in the examples above was symmetric andlinear, as illustrated in FIG. 28A, where line dashed line “n”represents the subject's normal body temperature (typically about 37degrees Centigrade). Modeling of the vestibular system indicates thatwaveforms of similar amplitude and frequency, but with a variation inshape, are also effective, such as the “logarithmic” or “convex”waveform of FIG. 28B, and the “exponential” or “concave” waveform ofFIG. 28C. All waveforms generally include a leading edge (“le”), atrailing edge (“te”), a peak (“p”) and a trough (“t”).

While FIGS. 28A through 28C all show three consecutive waveforms of thesame shape, amplitude, and frequency, the consecutive waveforms can bevaried in shape as shown in FIG. 28D, and can be varied in amplitude orduration as well (preferably each consecutive waveform within theparameters noted above), to produce still additional waveforms andsequences of waveforms which are useful in carrying out the presentinvention.

In addition, while the waveforms of FIGS. 28A through 28D are shown ascontinuous, minor disruptions can be included therein, such astruncations (“trn”; for example, as shown in FIG. 28E) or vertical cuts(“ct”; for example, as shown in FIG. 28F) to produce still additionalwaveforms and sequences of waveforms which are useful in carrying outthe present invention.

The peak for all waveforms of FIGS. 28A-28E is cooling by 17 degreesCentigrade from normal body temperature to a temperature of 20 degreesCentigrade, and the trough for all waveforms is a return to normal bodytemperature, giving an amplitude of 17 degrees Centigrade. The frequencyfor all illustrated waveforms is 1 cycle (or one complete waveform)every five minutes. While 3 cycles of the same waveform are illustratedfor clarity, note that in some of the examples above only two cycles aredelivered over a total treatment or session duration of ten minutes.

Example 11 Patient Orientation

It was noted that a patient who was sitting up (watching television) andreceiving a cold caloric vestibular stimulation (CVS) treatment reportedperceiving a different effect than perceived in prior sessions. Uponreclining to about 45 degrees, she did receive the earlier effect.

The “standard” angle of recline for diagnostic CVS is about 60 degrees(or equivalently 30 degrees above horizontal). The reason for thispositioning is that the “horizontal” SCC is tilted up by about 30degrees (higher on rostal side) (More recent x-ray measurements put theangle at closer to 20+/−7 degrees.) The intent with diagnostic CVS is toreorient the horizontal SCC so that it is substantially vertical, thusmaximizing the effect of the convective flow set up by calorics.

Hence, if the subject is reclined to about 20 degrees above horizontal(and supine), then a cold stimulus leads to inhibition or a phasic rateless than the tonic rate. For a warm stimulus, this situation isreversed (phasic rate increases above tonic).

Further, cold simulation tends to activate principally the contralateralbrain structures whereas hot leads to principally ipsilateralactivation. For example, in V. Marcelli et al. (Eur. Radiol. 70(2):312-6 (2009)), the authors did a left ear, cold stimulation by waterirrigation and saw right-side activation in the brainstem, cerebellum,etc. The patient was presumably nearly reclined in the MRI magnet.

Empirical tests and modeling indicate that approximately 20 degreesCentigrade absolute cooling (17 degrees Centigrade below bodytemperature) is the lower limit beyond which the cupula is maximallydeformed and therefore the phasic rate change is maximal. On the warmingside, more than about 7 degrees or so above body temperature becomesuncomfortable. This level of temperature heating within the ear canalwill not lead to maximal deformation of the cupula. Therefore, there isan asymmetry in terms of ability to span the full frequency spectrum ofphasic firing rates. However, the increase in the phasic firing rate isnot constrained in the manner of a decrease—that is, the phasic firingrate can only approach zero, relative to the tonic rate of roughly 100Hz, whereas the phasic rate can exceed 200 Hz.

Since inverting the patient changes the sign of theinhibitory/excitatory motion of the cupula, the following can be seen:Using a cold stimulus, of 20 degrees absolute, but now orient thepatient so that his head is tilted forward by from 75 to 20 degrees fromthe vertical position. This will invert the horizontal SCC relative tothe image above and now the cold stimulus will result in an excitatoryincrease in the phasic firing rate. For clarity, tilting the headforward by 20 degrees makes the horizontal SCC substantially horizontal.Tilting beyond that now starts to invert it so that at 110 degrees(tilted forward), the horizontal SCC will be in a vertical orientation,but now 180 degrees flipped from what is used in conventional diagnosticcaloric vestibular stimulation. So, the “general rule” for treatment ofhaving the patient reclined by 45-90 degrees can be expanded to include“tilted forward” by 75-120 degrees.

Thus a protocol is seen where, using only cold stimulus, one can coverthe entire range of phasic firing rates simply by reorienting thepatient at the appropriate points during the time course of treatment.

Note that this type of inversion should also lead to an inversion in theside of the brain that is primarily activated. Specifically, if coldstimulation leads to principally contralateral activation in the“rightside up” orientation, then it should lead to principallyipsilateral activation in the “upside down” orientation.

Example 12 Thermal Modeling of Caloric Vestibular Stimulation

Equation (4) of Proctor et al. (Acta Otolaryngol 79, 425-435, 1975) canbe extended for an arbitrary sequence of heating and/or cooling steps.Equation (4) is a fairly simple usage of the 1-dimensional diffusionequation. Therefore, the model is not exact. The temperature differenceacross the horizontal canal (i.e., the thermal driving gradient) isapproximated:

L=distance across horizontal canal (mm); default=6

T_(n)=difference between applied temperature and previous temperature (°C.)

a=“thermal diffusivity” of temporal bone (mm2/sec); this may vary inpatients, but compact bone paths will dominate the thermal. Theliterature lists values from 0.14-0.25, but this is based on the onsetof nystagmus as the “stimulation time.” Marcelli et al. showed a muchfaster, actual brainstem activation time after CVS, which did not relateto the onset of nystagmus. Literature estimates for the thermaldiffusivity of hard bone range from 0.45-0.55 to 1.6. A value of 0.5 isassumed here, based on x-rays of the compact, wet bone in the region ofinterest.

x=the effective thermal distance (mm) between external ear canal and theedge of horizontal semicircular canal; default=7.5 mm

ΔT=the temperature difference across the semicircular canal (° C.);distal minus proximal temperature.

t_(n)=time at which new stimulus starts.

Default values for the constants are listed next to the definitions. CVSapplication times that are short compared to the response time of thepatient may not be very different from a longer pulse at a lowertemperature due to thermal smoothing effects. Literature reports of themaximum phasic firing rate are about 100 Hz. That is, +/−100 Hz awayfrom the tonic firing rate, which is on the order of 100 Hz. The maximumdeformation of the cupula at its center is, correspondingly, about 77microns. Thermal gradients that imply a deformation greater than thisvalue would tend to lead to saturation of the phasic firing rate. At theother end of the scale, the minimum detectable volume change in the SCCis on the order of 25 picoliters and this corresponds to a change in thephasic rate of roughly 0.5 Hz. This indicates a minimum temperaturegradient across the SCC of −0.02° C. The obvious requirement is that thebody's homeostatic temperature regulation must ensure a constanttemperature across the 6 mm wide canal to a value on that order.

Another simplification used in the model was to ignore the temperaturedependence of the bulk coefficient of thermal expansion of water (withthe simplifying assumption that endolymph has roughly the thermalproperties of water). This assumption will lead to an apparentsaturation of the phasic firing rate at higher temperature (roughly 27°C.) than will actually occur. Below body temperature, the phasic ratemay not saturate until the lower 20's.

The volume of the horizontal SCC is estimated to be: 3.2E-3 cc. Thechange in volume due to a temperature difference ΔT is:3.8E-4*3.2E-3*ΔT=1.22E-6 ΔT.

The volume of the “lens” of the cupula when deformed to its maximal(saturation of the phasic firing rate) extent is roughly: 4.4E-6 ccTherefore, the change in the phasic rate: Δf=27.7*ΔT in Hz.

The relationship between the applied thermal waveform and the phasicfiring rate of the afferents of the vestibular branch of the 8th cranialnerve can thus be modeled for a square waveform stimulus (such as inExample 1 above) as shown in FIG. 29 herein, and for a time-varying, sawtooth, waveform stimulus (such as in Example 2 above) as shown in FIG.30 herein.

Note that there is little distortion of the time-varying waveform ofFIG. 30, as compared to the square waveform of FIG. 29, because the bodycan track the more gradual temperature changes.

There is a tendency for the values to skew a small amount vertically(e.g., the temperature delta goes slightly above body temp at points).This effect appears to be non-physical and is simply a limit of theapproximate model employed. The same appears true of the firing rategoing positive.

The “tips” of the sawtooth waveforms appear to exceed the maximum changein phasic firing rate of 100 Hz (this is seen in the square wave aswell). This may be because the coefficient of thermal expansion of theendolymph changes with temperature and was not corrected in the modelabove. This would result in an overestimate of the firing rate for agiven temperature in the plot. Therefore, the firing rate may not, infact, saturate (i.e., will stay below a delta of 100 HZ) at 20 C. Theloss of a sense of improvement reported in Example 3 above fortemperatures below about 17 to 20 degrees Centigrade may be due to thecupula of the vestibular canal “pegging” (achieving its maximal physicaldistortion) and the firing rate saturating.

Example 13 Treatment of Chronic Migraines and Refractory Depression

A female subject was a headache sufferer with a 10-year history ofdebilitating, chronic migraines, the last five being refractory. She hadfailed all pharmaceutical interventions. The patient underwent anoccipital nerve stimulator implant for headaches, with goodsymptom-management for approximately one year, at which point the devicewas no longer effective. Co-morbid with her migraine headaches wasdepression, which was only partially responsive to pharmaceuticalmanagement. Subject was placed on disability from her employment.

The subject was treated using a five-day therapy paradigm consisting ofdaily treatments comprising a square waveform pattern of cooling to 20degrees Centigrade, at a frequency of one cycle every ten minutes, for atotal duration of ten minutes while the patient was in a reclinedposition of thirty degrees above horizontal. Video images of the subjectwere captured before, during and after each treatment session and wereused to assess the effectiveness of the treatment (e.g., by assessingthe patient's mood).

For all active, in-process migraine episodes, within 5-15 minutes aftercompletion of a treatment, subject experienced pain attenuation. Chronicheadache indication was alleviated on the 4^(th) day of treatment, withconcurrent progressive improvement in her mood over the course of thefive days. The treatment course peaked at day 5. The subject becamepain-free, with complete resolution of mood symptoms. She remainedpain-free for 63 days after the therapy was completed, at which time hermigraine headaches began to recur, but without return of clinical moodsymptoms.

The five-day therapy paradigm was repeated. The subject responded morequickly to this second longitudinal therapy, with her chronic headachesdisappearing on the 3^(rd) day of treatment. She remained pain-free forfive weeks.

Later, the patient was treated with a sawtooth waveform (FIG. 31) (lowertemperature of 20° C.) employing a daily treatment duration of 10minutes. By the end of the treatment week, the patient was pain free(using a 0-3 pain scale where 3 is severe, 2 is moderate, 1 is mild, andzero is no pain). The chart (FIG. 32) shows pain scores, each day,pre-treatment, immediately after treatment, and 2 hours after treatment.All CVS treatments were to the right ear using cold stimulation.Additionally, after each treatment week, the patient stayed pain freefor times varying from 2-9 weeks. The patient additionally reportedfeelings of high energy and resolution of co-morbid depression.

Example 14 Treatment-Associated Dizziness in Migraine Patient

The same subject described in example 8 had right ear CVS treatmentusing a heating, to approximately 42-43 degrees, sawtooth waveform for10 minutes as illustrated in FIG. 33, with a contiguous repeat for anadditional 10 minutes. The treatment was effective in resolving heracute migraine pain. Additionally, the treatment had a soporific effectbut also caused slight dizziness. The subject did not note the feelingof dizziness in example 8 using cold stimulation.

Example 15 Treatment of Cluster Headache and Treatment-AssociatedDizziness

The same subject described in example 1 underwent the same CVS treatmentdescribed in example 14. He too reported a feeling of slight dizzinessthat was not apparent during cold CVS stimulation.

Example 16 Vestibular Migraine Treatment in Female Patient

A female subject in her late 30's had a history of migraine withassociated vertigo (vestibular migraine). The subject has a history ofvestibular dysfunction and slight co-morbid depression. The subject wastreated on a near daily basis, between 20-40 minutes per day, with coldstimulation (down to 20° C.) CVS before switching to warm CVS, with amaximum temperature of 48° C. All CVS treatments used a sawtooth patternwith left-ear stimulation due to more severe vestibular dysfunction inthe right ear. This subject did not note dizziness as a side effect ofthe warm CVS treatment, suggesting that her vestibular system, due todysfunction, is more immune to CVS (and thus she must treat moreaggressively to gain benefit). A parent of the subject commented on achange in the subject's speech and “spirit” during phone conversationswhile using cold CVS. The switch to warm CVS resulted in additional moodand motivational elements. Colleagues commented on enhancedinterpersonal interactions and an increased sense of confidence. Thesubject stated: “for the last couple of year I've felt as if my brainhas burnt out, it feels so much better since the warm treatments.”

Example 17 Vestibular Migraine Treatment in Male Patient

A male in his 40's developed sudden onset migraine with vestibulardysfunction that led to effective disability and inability to go towork. The subject was not helped by medications and sought the advice ofmultiple physicians at two prominent academic research hospitals. Thesubject was treated on a near daily basis for 10-20 minutes a day withcold CVS (down to 20° C.) CVS before switching to warm CVS, with amaximum temperature of 42° C. The subject, like the subject in example16, did not experience dizziness with the introduction of warm CVStreatments, possibly associated with the vestibular dysfunctionaccompanying his migraines. CVS treatments are soporific for thispatient. The subject's wife notes a pronounced change since CVStreatments were started. Whereas prior to CVS treatment the subject wasloath to get out of bed, since CVS treatment the subject has returned topart-time work with his employer.

Example 18 Treatment of Diabetic Patient with Warm Sawtooth Stimulation

The same subject described in example 9 switched from cold CVS to warmCVS for the control of his type II diabetes. He treated with a sawtoothwaveform that oscillated between 34 and 43° C. The average heating slewrate was typically above 40° C./min and the average cooling slew ratewas typically greater than 10° C./min. Since commencing CVS therapy, thesubject has stopped taking medications, which were previously necessaryto maintain serum glucose near a normal range. At the time of diagnosis,the subject's A1c value was 9.8. At the time shown at the end of thechart below, that value was reduced to 5.6 (again, with no medications).A1c is viewed as a better long-term marker of diabetes control thanserum glucose (it doesn't fluctuate). The normal range is about 4-6. Fordiabetics, the recommendation is that anything below 7 is a good target.The chart in FIG. 34 shows a record of the subject's serum glucosereadings and the possible additional improvement realized with theswitch from cold to warm CVS in terms of reduced variability. Thesubject also had a gingival abscess during the period shown and suchinfections can lead to oxidative stress and impaired glucose control(see generally J. Southerland et al., Diabetes and PeriodontalInfection: Making the Connection, Clinical Diabetes 23, 171-178 (2005)).The infection did not disrupt the subject's glucose maintenance.

Glucose readings taken at 7 AM and 10 PM; CVS treatment in evening.Treatment 1: 34 to 17 degree C. sawtooth waveform, 20 minute duration.Treatment 2: 34 to 43 degree C. sawtooth waveform, two 20 minutetreatment per day. Glucose levels are more controlled with treatment 2.No other diabetes medications were in use during the testing period. Thesubject reported that the warm sawtooth CVS differed slightly from thecold sawtooth CVS in that it appeared to have increased potency as notedby the feeling of increased dizziness and mild nausea, which appearconsistently with each treatment. Glucose levels tend to drop 10-30points approximately 60 minutes or more after the treatment. The subjectreported that combining exercise in proximity to the TNM therapyappeared to cause a glucose decrease of 30 to 50 points.

Example 19 Treatment of PTSD Patient

A male in his mid 60's was wounded three times as a Medic in Vietnam andhad a history of post-traumatic stress disorder. His manner is describedas introverted and his mood depressive. After the commencement of coldCVS treatments, the subject's wife reported that he started becomingmore extroverted. She reported that “she did not know who this personwas speaking to her this morning”; that he was planning getting togetherwith friends; that usually he would only do this if forced; that heexpressed interest in going to Africa for a photo safari; that shestarted thinking “where is my husband?” After a second treatment, thesubject reported continuous sleep throughout the night (usually he wouldusually wake up 3-4 times). He commented that “insomniacs should usethis.” The subject reported feeling energized. The subject was usuallyunable to recall dreams, but awoke with visual flashback of events inVietnam, not unpleasant just old visual memories, and returned to sleep.The subject traditionally avoided driving but now is driving withsubstantially less hesitation. The subject is a serious amateur painterand both the subject and his spouse report significant positivedevelopments in his painting style and productivity since commencementof his CVS. Upon interruption of CVS therapy, PTSD symptoms graduallyreturned almost to baseline one week after CVS stopped.

Example 20 Treatment of Diabetes in a PTSD Patient

The patient of example 19 has type II diabetes. After the commencementof CVS therapy he became much more responsive to oral hypoglycemics, hashad to cut dose significantly as indicated in the chart in FIG. 35.

Example 21 Alternative Waveforms in Treatment of Diabetes and ClusterHeadaches

The patient described in example 18 above was administered threedifferent waveform CVS stimuli, as follows:

A: Cooling, by approximately 22-23 degrees, with a spike waveform for 10minutes as illustrated in FIG. 36, with a contiguous repeat for anadditional 10 minutes.

B: Heating, to approximately 42-43 degrees, with a spike waveform for 10minutes as illustrated in FIG. 37, with a contiguous repeat for anadditional 10 minutes.

C: Cooling, to approximately 22-23 degrees, with a spike waveform for 10minutes as illustrated in connection with A above, followed immediatelyby heating, to approximately 42-43 degrees, with a spike waveform for 10minutes as illustrated in connection with “B” above.

The treatments seemed to have a bimodal pattern of efficacy based uponcooling or heat cycles. Both modes seem to induce a sense of motion andmild nausea associated with enhanced therapeutic efficacy for thetreatment of cluster headaches and the stabilization of type II diabetesin this subject. Pattern A appeared to be the most efficacious.Increasing cycle times to thirty minutes does not appear to confer anadditional benefit.

Example 22 Induction of Prolonged Nystagmus by Waveform CVS

Nystagmus is the name given to involuntary eye movements enabled by theso-called vestibulo-ocular reflex (VOR). CVS provides an artificialmeans to activate the VOR. By tilting the head (˜20 degrees above thehorizontal), the horizontal SCC is placed in a vertical orientation.Creating a differential temperature across this canal results inconvection currents that act to displace the cupula. Warm CVS leads tocupular displacement such that the phasic firing rate increases whereascold CVS leads to a decrease in the firing rate. Further, warm CVSresults in nystagmus that is manifested by a rapid movement of the eyestowards the simulated ear. Cold CVS results in the rapid phase ofnystamus away from the stimulated ear. Therefore, by noting theexistence and the direction of nystagmus, one may determine that the VORis being activated and whether the phasic firing rate is greater than orless than the tonic firing rate.

The use of continuous CVS irrigation or stimulation at a constanttemperature will induce nystagmus, but after a time on the order of 2-3minutes (e.g, Bock et al., Vestibular adaptation to long-term stimuli,Biol. Cybernetics 33, 77-79 (1979)), the cupula will adapt to its new,displaced position and the phasic firing rate will return to the tonicrate. Thus nystagmus will effectively cease and the vestibular nerveafferents will no longer be stimulated.

It is an aspect of the current invention that the use of time-varyingthermal waveforms enables the persistent stimulation of the vestibularnerve afferents, beyond the time period at which adaptation to aconstant thermal stimulus occurs. In this example, the present inventionhas been used to generate nystagmus over a 12 minute period as measuredby videonystagmography and by electronystagmography. A sawtooth coolingwaveform going between temperatures of 34 to 20° C. was applied to theright ear of a subject who was reclined such that his head was ˜20degrees above the horizontal. Electronystagmography was used to measurethe movement of his eyes. Segments of the time series of the nystagmusare shown in FIG. 38A (early segment) and FIG. 38B (late segment),demonstrating the existence of nystagmus both early in a 12 minuteperiod and near the end of the 12 minute period.

Example 23 Effect of CVS on Regional Cerebral Blood Flow (rCBF)

The purpose of this Example is to find a robust marker of successful CVSinduction of relevance to neurological treatments. The study is beingperformed on rats using a modified version of a dual ear CVS unit.Specifically, ear bars that are connected to TEC's are placed in the earcanals of rats that have been anesthetized. The device has dual earstimulation capability.

Methods and Results:

Single ear CVS: Rat #9 received a sawtooth waveform in the right earthat oscillated between 36 and 14° C. for 60 minutes (FIG. 39). The ratwas anesthetized with isoflurane. It should be noted that anesthesia maylessen the effects of CVS to a degree. The rat was orientedhorizontally, which places the horizontal semicircular canal in thevestibular bodies at a roughly 30 degree tilt upwards on the anteriorside. After the end of the 60 minute right ear stimulation, the samecaloric waveform was then applied to the left ear. The plot in FIGS.40-418 shows the response of the regional cerebral blood flow asmeasured on the right parietal region of the skull via a laser Dopplerprobe affixed to the skull. Roughly 30 minutes after the start of rightear CVS, the oscillation in blood flow became pronounced. The period ofthe sawtooth temperature waveform is 1.9 minutes. As seen in the graphin FIG. 42 (using nearest neighbor averaging), the period of themodulation in blood flow is longer, by about 30 seconds on average. Thissuggests that the driving force (the CVS) leads to modulation of theblood flow via a mechanism that stays in a non-equilibrium state. Thatis, the rat's response does not simply match the period of the CVSwaveform and is instead adapting to it dynamically. At the end of rightear CVS, the oscillations stop. Roughly 35-40 minutes after the start ofleft ear CVS, clear oscillations once again appear, though diminished inamplitude relative to right ear stimulation. This is presumably due tothe fact that left ear stimulation has a weaker effect on blood flow inthe right portion of the brain. Serrador et al. (BMC Neuroscience 10,119 (2009)) note that “connections have been found between thevestibular nuclei and the fastigial nucleus . . . followed byvasodilatory connections to the cerebral vessels.”

Control Run:

The data in FIG. 43 show the results from a control run wherein the CVSdevice was placed on the rat, but was not activated. No oscillations inrCBF were seen (the downward drift in the flow data is due to a slightshift in the baseline of the probe).

Dual Ear, Same Waveform:

Rat #12 had CVS delivered to both right and left ears simultaneously(FIG. 44). The waveforms were not tied in phase and tended to become outof phase during the bulk of the 60 minute treatment period. Nomodulations in rCBF were manifested (FIG. 45).

The dual ear stimulation data suggest that the application of the samewaveform to both ears simultaneously acted to cancel out any netmodulatory effect on rCBF. However, it is still the case that the samestimulation was given to the vestibular nuclei as when only single earCVS was used. Nystagmus, would also not appear if the same CVSstimulation were applied to both ears since the phenomenon, mediated bythe vestibulo-ocular reflex (VOR), requires a differential input to thetwo horizontal SCC's. Thus the absence of rCBF modulation does not meanthat the fastigial nuclei (both nuclei for dual ear CVS) are not beingstimulated. Rather, their combined activation yields no net effect onrCBF. Since modulation of rCBF is not a necessary aspect of CVS inducedneuroprotection (it is a marker of CVS induction), CVS therapy mayactually be as or more effective with dual ear stimulation.

Dual Ear, Different Waveforms:

Run 17 simultaneously applied a 34 to 44 C sawtooth waveform to theright ear (period of −40 seconds) and a 34 to 13 C sawtooth (period ˜1.7min.) to the left ear (FIG. 46). In this case, flow modulations wereseen and they persisted well past the end of the CVS treatment period(FIG. 47). In this case the flow effect, with different temperaturesapplied, not only was present but continued to oscillate after the endof the active CVS treatment.

Summary:

The vestibular systems of all mammals act in the same way. Therefore,the results of the rat study discussed above has implications for humanCVS therapy as well. The conclusion from the study is that the mostlikely cause of the modulation seen in rCBF is that CVS does stimulatethe fastigial nucleus in the cerebellum.

Example 24 EEG in Rats as a Metric of CVS Efficacy

EEG is useful in identifying cortical activation associated with CVS.Therefore, EEG is useful as a non-invasive means to titrate CVS therapy.This report summarizes EEG data acquired in a rat study.

Methods and Results:

The report on regional cerebral blood flow changes in a rat duringvarious CVS treatments has been generated. In this summary, EEGelectrodes were placed in the scalp of the rat, differential pairs beingapplied on either side of the midline of the skull. The plot in FIG. 48shows the resultant change in activity when comparing the baseline(prior to CVS starting), “high” flow, and “low flow” conditions, wherethe oscillations in regional cerebral blood flow are the markers ofchange. The CVS stimulus was a 34 to 13° C. sawtooth applied to theright ear.

Discussion:

As can be seen in the 0-12 Hz plot above, the activity in the theta bandwas markedly different between the 3 states. For the low flow state,activity was depressed. The high flow peaks were shifted to lowerfrequencies as compared to the baseline (pre-CVS). In the 0-40 Hz plot,the high and low flow peaks in the low-30 Hz range overlap whereas thebaseline peak is shifted (this is likely due to a difference insomatosensory perception during CVS versus pre-CVS). The sensitivity ofEEG spectra to the details of CVS delivery suggest that EEG is aneffective tool for evaluating the difference between CVS waveforms andfor titrating them.

Example 25 Heart Rate Variability (HRV) as a Metric of CVS Efficacy

Heart rate variability seems to be a significant marker of health andsystems for measuring it non-invasively are becoming common. This reportdescribes the use of the ithlete, a commercial HRV measurementinstrument that runs as an smartphone software program, or “app.”

Methods and Results:

The subject is a 40-45 year old male diagnosed with seasonal clusterheadaches. The device used to measure HRV is the ithlete (HRV Fit Ltd.,Hants UK)) which uses an iPhone as the recording/readout device and achest strap with sensors that monitor heart rate. The HRV parameter iscalculated via a proprietary algorithm that takes the raw heart ratedata as input. Note: of course there are many devices that will measureHRV and the ithlete was chosen only as a low cost and convenient system.Proper HRV is used as a metric of proper cardiac health (good healthimplies adequately high HRV; e.g. Malik, “Heart rate variability:standards of measurement, physiological interpretation, and clinicaluse,” Eur. Heart Journal, vol. 17, pg. 354, 1996). For example, Gujjaret al. have linked HRV and outcomes after acute severe stroke (“Heartrate variability and outcome in acute severe stroke,” NeurocriticalCare, vol. 1, pg. 347, 2004).

The CVS treatment was a 42° C. sawtooth wave applied to the left ear anda 17° C. sawtooth applied to the right ear. The treatment lasted for 10minutes. HRV data were recorded immediately after the end of thetreatment. HRV is a dimensionless measure. During the October 24^(th)test, average HRV dropped by 30% and on October 28^(th) by 27% (see FIG.49).

Discussion:

HRV is proposed as a marker of effective CVS induction and could thus beused as a tool for titrating CVS dosing. Pathological conditions (suchas cluster headaches discussed here) can lead to elevated HRV levels.Other pathological conditions, e.g. cardiac insufficiencies, are oftenassociated with abnormally low HRV values (for that individual).

Example 26 Treatment of Fibromyalgia

A subject (also female, age 50-55) was diagnosed with fibromyalgia 3years ago. Multiple allopathic and homeopathic interventions provided nosubstantive relief. The subject has co-morbid migraine headaches.

Methods and Results:

The subject underwent CVS treatment in the right ear, with a 17 deg C.sawtooth waveform. The subject's migraine pain scores versus time arelisted in FIG. 50.

From September 13-19 the subject stopped CVS treatment due tosignificant pain and inability to function. On September 20 the subjectbegan treatments twice per day, sometimes using a 3^(rd) daily treatmentusing the CVS parameters listed above. She realized an improvement inboth migraine pain and pain from fibromyalgia. In the September 28-30timeframe thunderstorms seemed to trigger additional migraine pain, butthis abated over the following days until her pain level was barelynoticeable.

The subject commented upon starting twice-a-day treatments: “I'm writingto report excellent results using 2 treatments. Last night I tried 2consecutive treatments, and I felt great! Like I'd been to a spa and hada relaxing massage and soak in the hot tub.”

The subject reported on September 26^(th): “This weekend I was able towork with [husband] getting 14 new bushes in the yard and picking outnew paint at Lowe's to repaint the shutters on the house. I'm so veryhopeful and happy. Gardening is a shared passion for us, and the firsttwo years here, I wasn't able to even water the plants, so the ones leftare real survivors! I feel like you are giving me my life back andgiving [husband] his wife back.”

When the subject's spouse was asked if the CVS device was truly helpfulhe responded: “Nothing in the last 3 years had helped before this.”

After October 6, the unit was retrieved. The subject has since returnedto baseline.

Example 27 Treatment of Peripheral Neuropathy

A female subject underwent spinal surgery and sustained damage to thespinal cord. Thereafter she has had intractable peripheral neuropathy(foot pain) over a roughly 4 month period that had not responded toanalgesics. The subject has obtained relief using CVS, with the extentand duration of relief depending on the device used and the waveformdetails.

Methods and Results:

The subject underwent CVS treatment with the following chronology:

1. Dual ear CVS unit: L-ear, sawtooth, 34 to 20° C.; R-ear, sawtooth, 34to 42° C., 10 min therapy. The treatment made her very sleepy (deepsleep for 20 min). Within 30 minutes, she was pain free and stayed sofor 3 days, which was extraordinary for her.

2. Single (right) ear CVS unit, sawtooth, 34 to 17° C., 10 min therapy.She realized about a 50% reduction in pain level that lasted around 2hours.

3. Single (right) ear CVS unit, long (single rise) square wave, 34 to48° C., 10 min. She finds that the single ear, warm treatment is betterthan single ear, cold treatment. She must use the device several times aday to achieve pain relief.

4. Dual ear CVS unit, L-ear 17° C. square wave, R-ear 44° C. sawtooth,10 min. Deep sleep for 45 min (at 5 PM). Foot pain ceased.

Discussion:

The subject received extended (multiple day) pain relief from one 10 minsession using dual ear CVS. Single ear CVS, using a sawtooth waveform(slower slew rate) and an early device (basically a single cold/warmsquare wave), led to partial pain reduction for a time limited to hours.Therefore, the dual ear CVS treatment was superior to single ear forpain reduction. This subject and another have stated that the mixedwaveform, dual ear (e.g., example 4) results in more significantsubjective sensations (deep relaxation/sleep for this subject, increasednausea for the other). It is unclear with this single case if the mixedwaveform treatment leads to increased pain reduction efficacy (both dualear treatments were significant).

Example 28 Single Ear Treatment of Episodic Migraine

This Example evaluates the feasibility of using a portable CVS unit in ahome setting over a month or more. The hypothesis was that daily CVStreatment would reduce the overall pain level and frequency ofheadaches.

Methods and Results:

The subject is a 50-55 year old female with a history of 6-8 migraineheadache days per month (a month is taken as 28 days when reporting onmigraine frequency). The subject used a right-ear CVS device and asawtooth waveform that went from 34° C. to 17° C. with a period ofroughly 1.7 minutes. The duration of the treatment was 10 minutes persession (daily sessions, moving to every other day after about 2 weeksof treatment). The average slew rate for heating was 40° C./minute andthe average slew rate for cooling was 14° C./minute.

The subject experienced a decrease in pain over the first week oftherapy. (pain scores in FIG. 51). In the 40 days past the one weektransitionary period, the subject had only one migraine headache (again,to qualify as a migraine it must be at a pain level of 6 or more on ascale of zero to ten and last for 4 hours or more). The one headacheoccurred during unusual stress associated with a transatlantic trip anddisruption of work schedule upon her return. The subject also noted asubjective improvement in co-morbid depression over the treatmentperiod.

Example 29 Titration of CVS Therapy for Type II Diabetes

The intent of this report is to show experimental evidence of thecontrol of glucose levels by adjusting the frequency with which CVS isused in a subject with type II diabetes.

Methods and Results:

The subject is a 40-45 year old male diagnosed with type II diabeteswithin the last two years. As reported earlier, the subject has beenable to forego the use of medications to control serum glucose levels,using CVS therapy instead. Recently, the subject has started using dualear CVS, with a warm time-varying waveform applied to one ear and a coldtime-varying waveform applied to the other. The dual ear therapy reducedthe frequency with which the subject needed to use CVS in order tocontrol serum glucose levels as shown in the graph in FIG. 50. Dual earCVS was used with a 17° C. square wave for the right ear and a 42° C.sawtooth on the left ear. Each point in the graph represents a dailymeasurement (consistent time during each day). The red lines show whenCVS was used. As the glucose levels were tracked, they would tend tomove up in between CVS treatments, thus signaling when another treatmentshould be applied. This feedback method should be able to be extended toother patients, using their specific glucose levels to titrate frequencyand intensity of CVS treatments. This subject remains off any othermedications to control glucose levels.

Discussion:

This is an update report to supplement accounts from this subjectalready included in the Examples above, and further shows that serumglucose is a useful metric for CVS titration.

Example 30 CVS Intensity for Different Waveforms

As the CVS treatment device has evolved, we have moved from single todual ear stimulation and have increased the slew rate to allow waveformsto be played out at a higher frequency. This report lists subjectivemetrics that can be used to assess the strength of CVS stimulation for agiven subject.

Methods and Results:

The subject is a 40-45 year old male using CVS therapy chronically fortype II diabetes and seasonal cluster headaches. He ranks the level ofintensity of the CVS experience as follows:

single ear:

-   -   daily treatments were required to control cluster headaches and        serum glucose levels    -   typical treatment is a cold sawtooth wave going between 34 and        17° C.

dual ear, same waveform shape, warm and cold:

-   -   only 1-3 treatments per week are needed to control cluster        headaches and serum glucose    -   typical waveform is a sawtooth going from 34 to 42-44° C. in one        ear and 34 to 17° C. in the other ear.    -   Not much subjective difference compared with single ear during        treatment        -   More pronounced dizziness upon standing        -   Nausea more persistent        -   Faster, more complete responses for increased pain level        -   Blurred vision for 3-5 minutes (possibly nystagmus)

dual ear, different waveform shape, warm and cold:

-   -   only 1-3 treatments per week are needed to control cluster        headaches and serum glucose    -   typical waveform is a sawtooth going from 34 to 42-44° C. in one        ear and a square wave in the other ear going from 34 to 17-20°        C.    -   most potent of all types tried in terms of pain mitigation and        positive mood effects (side effects do not outweigh additional        benefits)        -   sleep inducing        -   nausea while in horizontal position        -   significant nausea and brief period of poor postural control            upon standing        -   persistent feeling of head fullness

Discussion:

The most significant metrics for CVS therapy for pain patients is itseffects on pain level and relative side effects. This report recountsobservations by one subject that can serve as a paradigm for how otherpatients can be assessed in the clinic. The right titration will involvean on-going assessment of effects on symptoms (e.g., pain) andminimization of unwanted, lasting side effects (for clarity, the sideeffects reported above are transient). There are tradeoffs that patientscan make between efficacy with more intense side effects balancedagainst less frequent need to treat.

The following parameters can be varied in a dual ear system:

-   -   1. temperature (magnitude and sign with respect to body        temperature)    -   2. waveform shape    -   3. frequency of waveform(s); if they are different frequencies,        they could be commensurate and beat frequencies could be        established.    -   4. relative phase of waveforms (e.g., in phase or some degree of        being out of phase if they have the same frequency)    -   5. variable frequency during the course of a treatment (each        side)        The CVS device can be programmed, in principal, to play out a        different combination every day, thus frustrating any tendency        of the VS of the patient to adapt to a given therapeutic        waveform. This is a principal advantage of dual ear over single        ear CVS.

Example 31 Treatment of Sleep Disorders/Insomnia with CVS

A common report from users of the CVS device is that they havebeneficial effects in terms of sleeping soundly. It is known (e.g.,Horii et al., J. Neurophysiol, 70, 1822, (1993)) that CVS does activatethe hypothalamus. The hypothalamus in turn controls the sleep/wake cyclein mammals.

Methods and Results:

The reports of the soporific effects of CVS with subjects is variableand subjective. Listing the claims by subjects in order of frequency:

1. a relaxed feeling right after the completion of a CVS treatment

2. report of having an exceptionally complete sleep cycle on the nightfollowing a CVS treatment

3. A very powerful soporific effect that resulted in the subject fallingasleep during a 10-20 minute CVS treatment and staying asleep for up toseveral hours.

Examples of Each of the Observations Listed Above:

1. A small pilot clinical trial was performed at a private headacheclinic on patients who were being treated for migraine headache. The CVSwaveform used was a sawtooth, right ear only, with the temperatureoscillating between 34 and 17° C. None of the subjects fell asleepduring the 10 minute CVS treatment, but commonly reported being relaxedin a way that was greater than what they would feel when lying down, ina similar position, for the same amount of time.

2. A male, age 50-55 acting as a normal test subject used single ear(right) CVS, sawtooth waveform oscillating between 34 and 17° C. Hereported pleasant drowsiness after the 10 minute therapy session andthen reported that he'd slept exceptionally soundly that night.

3. A subject using CVS for foot pain (see previous Example on thissubject) used a dual ear CVS device: L-ear, sawtooth, 34 to 20° C.;R-ear, sawtooth, 34 to 42° C., 10 min. therapy. The treatment made hervery sleepy (deep sleep for 20 min). Then again: dual ear, L-ear 17° C.square wave, R-ear 44° C. sawtooth, 10 min. Deep sleep for 45 min (at 5PM) and had to be awakened.

In all cases, subjects reported restful sleep versus “forced” sleep andthey reported no ill side effects.

Example 32 Single Ear CVS Treatment of Pediatric Epilepsy

The intent with this study was to evaluate using the Gen 2.0 CVS unit(left ear only, same earpiece but different (less powerful) TEC(thermoelectric cooler or Peltier cooler) than will be used in Gen 3device) in a single session to observe any effects on spike activity inepileptic patients as monitored by EEG.

Methods and Results:

The subjects were treated with a sawtooth waveform that went from 34° C.to 17° C. (left ear only). Note that the actual temperature profile wasnot the same for all patients. For patient 3, the average slew rate onheating was around 14-15° C./min and the cooling rate dropped from about5.8° C./min to 4.5° C./min (FIG. 51). It can be seen that more time wasrequired to in the second “dip” to get to 17° C. This is due toinsufficient power in the Gen 2.0 CVS device.

For patient 4, the inadequate power of the unit is even more apparent.The average heating slew rate was about the same as with patient 3, butthe cooling rate started at 4.2° C./min and dropped to 3.6/min (notshown). The device failed to reach the 17° C. target temperature.

The spike rate, as measured by continuous EEG, of the baseline (beforeCVS treatment) versus post CVS treatment is shown in FIG. 52. Thedecrease in spike rate lasted from 1-2 hours for each of the fourpatients. The reduction in spiking ranges from 21-32%.

Discussion:

despite the underperformance of the Gen 2.0 model, primarily caused byan older, less powerful TEC and the lack of a cooling fan on the heatsink, demonstrable effects were seen in all 4 patients in terms of areduction in spike activity that persisted past the end of the CVStreatment session. At this time, we don't have the ability to try a moreadvanced device (e.g., Gen 2.5) with these patients. A logical coursewould be to treat the patients longitudinally to see if the effects ofCVS could be made more lasting. Despite the challenge of performing CVSon this population (age range from 6-10 years old), it was accomplishedand there were no side effects of the treatment.

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

That which is claimed is:
 1. A method of treating a subject afflictedwith Parkinson's disease and in need of treatment thereof, comprising:(a) administering said subject an active agent in a treatment effectiveamount; and concurrently (b) administering said subject caloricvestibular stimulation in a treatment effective amount, said caloricvestibular stimulation administered so as to enhance the efficacy ofsaid active agent, wherein said caloric vestibular stimulation isadministered as an actively controlled time varying waveform and thesubject is afflicted with Parkinson's disease.
 2. The method of claim 1,wherein said active agent is administered orally.
 3. The method of claim1, wherein said active agent is selected from the group consisting of:levodopa, carbidopa, amantadine, pramipexole, ropinirole, pergolide,cabergoline, apomorphine, bromocriptine, MAOB inhibitors, COMTinhibitors, alpha-2 inhibitors, anticholinergics, dopamine reuptakeinhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists, andinhibitors of neuronal nitric oxide synthase, and equivalents andpharmaceutically active isomer(s) and metabolite(s) thereof.
 4. Themethod of claim 3, wherein said active agent is a MAOB inhibitorselected from the group consisting of: selegine and rasagiline.
 5. Themethod of claim 3, wherein said active agent is a COMT inhibitorselected from the group consisting of: entacapone and tolcapone.
 6. Themethod of claim 3, wherein said active agent is an anticholinergicselected from the group consisting of: benztropine, biperiden,orphenadrine, procyclidine, and trihexyphenidyl.
 7. The method of claim1, wherein said caloric vestibular stimulation is administered for atime sufficient to induce nystagmus over a period of at least fiveminutes.
 8. The method of claim 1, wherein said caloric vestibularstimulation comprises a first thermal waveform delivered to a first earcanal of the subject.
 9. The method of claim 8, wherein said caloricvestibular stimulation comprises a second thermal waveform delivered toa second ear canal of the subject.
 10. The method of claim 9, whereinthe first and second thermal waveforms are different.
 11. The method ofclaim 1, wherein said active agent comprises a medication for treatmentof Parkinson's disease, the symptoms of Parkinson's disease or acombination thereof.